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  • 1.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

  • 2.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Vauquelin, Georges
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr22008In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 14, p. 6924-6935Article in journal (Refereed)
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

  • 3.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 22, p. 8059-8071Article in journal (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

  • 4.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers2012In: International Journal of Hypertension, ISSN 2090-0384, Vol. 2012, p. 789671-Article, review/survey (Refereed)
    Abstract [en]

    The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

  • 5.
    Axén, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rönnholm, Harriet
    Kortesmaa, Jarkko
    Demaegdt, Heidi
    Vauquelin, Georges
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor2007In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 7, p. 434-444Article in journal (Refereed)
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

  • 6.
    Axén, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Demaegdt, Heidi
    Vauquelin, Georges
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands2006In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 12, no 11, p. 705-713Article in journal (Refereed)
    Abstract [en]

    The angiotensin IV receptor (AT(4) receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.

  • 7.
    Borhade, Sanjay R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundbäck, Thomas
    Jenmalm-Jensen, Annika
    Sigmundsson, Kristmundur
    Axelsson, Hanna
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Konda, Vivek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides2014In: ChemistryOpen, ISSN 2191-1363, Vol. 3, no 6, p. 256-263Article in journal (Refereed)
    Abstract [en]

    The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.

  • 8.
    Botros, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Q
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindeberg, G
    Frändberg, PA
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tomboly, C
    Toth, G
    Le Greves, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Endomorphin-1 and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP(1-7) in the rat spinal cord.2005In: Peptides, ISSN 0196-9781Article in journal (Refereed)
  • 9.
    Botros, Milad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Johansson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tömblöy, Csaba
    Toth, Geza
    Le Greves, Pierre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Hallberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Endomorphins interact with the substance P (SP) aminoterminal SP (1-7) binding in the ventral tegmental area of the rat brain2008In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 29, no 10, p. 1820-1824Article in journal (Refereed)
    Abstract [en]

    We have recently identified a specific binding site for the tachykinin peptide substance P (SP) fragment SP1-7 in the rat spinal cord. This site appeared very specific for SP1-7 as the binding affinity of this compound highly exceeded those of other SP fragments. We also observed that endomorphin-2 (EM-2) exhibited high potency in displacing SP1-7 from this site. In the present work using a [H-3]-labeled derivative of the heptapeptide we have identified and characterized [H-3]-SP1-7 binding in the rat ventral tegmental area (VTA). Similarly to the [H-3]-SP1-7 binding in the spinal cord the affinity of unlabeled SP1-7 to the specific site in VTA was significantly higher than those of other SP fragments. Further, the tachykinin receptor NK-1, NK-2 and NK-3 ligands showed no or negligible binding to the identified site. However, the mu-opioid peptide (MOP) receptor agonists DAMGO, EM-1 and EM-2 did, and significant difference was observed in the binding affinity between the two endomorphins. As recorded from displacement curves the affinity of EM-2 for the SP1-7 site was 4-5 times weaker than that for SP1-7 but about 5 times higher than that of EM-1. The opioid receptor antagonists naloxone and naloxonazine showed weak or negligible binding. it was concluded that the specific site identified for SP1-7 binding in the rat VTA is distinct from the MOP receptor although it exhibits high affinity for EM-2.

  • 10.
    Brolin, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diwakarla, Shanti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gröndbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 646, p. 15-20Article in journal (Refereed)
    Abstract [en]

    In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.

  • 11.
    Brolin, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat2018In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 167, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

  • 12.
    Carlsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ohsawa, Masahiro
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamei, Junzo
    Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors2010In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 626, no 2-3, p. 250-255Article in journal (Refereed)
    Abstract [en]

    We have recently explored the role of the tachykinin substance P neuroactive fragment substance P1-7 in the mediation of anti-inflammatory effects using a blister model in the rat paw (Wiktelius et al., 2006). We observed that this heptapeptide induced a dose-dependent inhibitory effect on the substance P-induced response, which was reversible by the non-selective opioid receptor antagonist naloxone. In the present study, we examined the ability of substance P1-7 to induce antihyperalgesic effects in streptozotocin-induced diabetic mice. We found that the substance P fragment strongly and dose-dependently produced antihyperalgesia in diabetic mice. This effect was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine. selective for the mu-, delta- or kappa-Opioid receptor, respectively. In addition, the anti hyperalgesic effect induced by substance P1-7 was partly reversed by a sigma(1) receptor agonist (+)-pentazocine. but not a a, receptor antagonist BD1047 ([2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(diamino)ethylamine), suggesting that involvement of the naloxone-sensitive sigma-receptor for the action of the SP related heptapeptides. These results suggest that hyperalgesia in diabetic mice may be, in part, due to the enhanced endogenous sigma(1) receptor systems in the spinal cord.

  • 13.
    Diwakarla, Shanti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reddy Vanga, Sudarsana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Shamsudin Khan, Yasmin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Ng, Leelee
    Pham, Vi
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundback, Thomas
    Jenmalm-Jensen, Annika
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Yeen Chai, Siew
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density2016In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed)
    Abstract [en]

    Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

  • 14.
    Engen, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Axelsson, Hanna
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Konda, Vivek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dahllund, Leif
    Sci Life Lab Stockholm, Drug Discovery & Dev Platform, Solna, Sweden..
    Otrocka, Magdalena
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Sigmundsson, Kristmundur
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden.;Duke NUS Med Sch, Program Cardiovasc & Metab Disorders, Singapore, Singapore..
    Nikolaou, Alexandros
    Vrije Univ Brussel, Dept Mol & Biochem Pharmacol, Brussels, Belgium.;Ctr Genom Regulat, Barcelona, Spain..
    Vauquelin, Georges
    Vrije Univ Brussel, Dept Mol & Biochem Pharmacol, Brussels, Belgium..
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jenmalm Jensen, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Lundback, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening2016In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 14, no 3, p. 180-193Article in journal (Refereed)
    Abstract [en]

    Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.

  • 15.
    Enhamre, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 523, no 1, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated that both growth hormone (GH) deficiency and diabetes are conditions associated with impairments in learning and memory processes. In this study, we investigated the effect of streptozotocin-induced diabetes on spatial learning in mice using the Barnes maze (BM). The expression of the GH receptor (GHR) gene transcript in areas of the brain associated with learning and memory were examined. The results indicated that the GHR gene transcript is up-regulated in the prefrontal cortex (PFC) of diabetic mice compared to controls. In addition, there was a significant correlation between the expression of GHR mRNA and performance in the BM during the acquisition phase in diabetic but not control mice. These results suggest that diabetes induces an imbalance in the GH/IGF-1 system leading to altered activity in the PFC and associated cognitive deficiencies.

  • 16.
    Enhamre-Brolin, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Growth hormone reverses streptozotocin-induced cognitive impairments in male mice2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 238, p. 273-278Article in journal (Refereed)
    Abstract [en]

    In recent decades, growth hormone (GH) replacement therapy in human subjects deficient in the hormone has resulted in a number of beneficial effects on cognitive performance. Studies in hypophysectomised rats report similar effects of GH treatment on learning and memory tasks. The purpose of this study was to investigate the ability of GM to reverse learning impairments in mice with streptozotocin (STZ)-induced diabetes. Diabetic and control mice were given recombinant human GM (rhGH) 0.1 IU/kg/day for ten consecutive days. In the latter phase of the treatment the cognitive abilities of the mice were tested using the Barnes maze (BM). A profound hormonal effect was seen when analysing the search patterns used by the animals in the maze. rhGH treatment significantly counteracted the cognitive disabilities expressed as lack of direct search strategies on the last day in the BM. In addition, the number of primary errors made by diabetic mice during the acquisition phase was reduced by rhGH treatment, although the primary escape latency was unchanged in these animals when compared to saline-treated diabetic animals. These results suggest that specific cognitive impairments induced by STZ, i.e. the disabilities seen in strategic behaviour, could be reversed by exogenous hormone treatment. Our findings highlight the influence of GH on brain function and in particular on cognitive behaviour related to learning and memory.

  • 17.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality2008In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 42, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    Some of the biological effects demonstrated after administration of substance P (SP) in vivo can indirectly be attributed to the fragmentation of the undecapeptide to its N-terminal bioactive fragment SP1–7. This heptapeptide (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is a major bioactive metabolite from SP that frequently exerts similar biological effects as the parent peptide but also, in several cases, completely opposite actions. Specific binding sites for the heptapeptide SP1–7 that are separate from the SP preferred NK receptors have been identified. In this study we demonstrate that (a) the C-terminal part of the SP metabolite SP1–7 is most important for binding as deduced from an Ala scan and that a replacement of Phe7 for Ala is deleterious, (b) truncation of the N-terminal amino acid residues of SP1–7 delivers peptides with retained binding activity, although with somewhat lower binding affinities than SP1–7 and (c) a C-terminal amide group as a replacement for the terminal carboxy group of SP1–7 and for all of the truncated ligands synthesized affords approximately 5–10-fold improvements of the binding affinities.

  • 18.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Discovery of Dipeptides with High Affinity to the Specific Binding Site for Substance P1-72010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 6, p. 2383-2389Article in journal (Refereed)
    Abstract [en]

    Substance P 1-7 (SP1-7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is the major bioactive metabolite of substance P. The interest in this heptapeptide originates from the observation that it modulates, and in certain cases opposes the effects of the parent peptide. e.g., the nociceptive effect. The p-opioid receptor agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) has been found to also interact with the specific binding site of SP1-7 with only a 10-fold lower affinity compared to the native peptide. Considering the smaller size of EM-2 compared to the target heptapeptide, it was selected as a lead compound in the development of low-molecular-weight ligands to the SP1-7 binding site. An alanine scan and truncation study led to the unexpected discovery of the dipeptide H-Phe-Phe-NH2 (K-i = 1.5 nM), having equal affinity as the endogenous heptapeptide SP1-7. Moreover, the studies show that the C-terminal phenylalanine amide is crucial for the affinity of the dipeptide.

  • 19.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nordvall, Gunnar
    Bylund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson-Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kratz, Jadel M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues2014In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, ACS medicinal chemistry letters, ISSN 1948-5875, Vol. 5, no 12, p. 1272-1277Article in journal (Refereed)
    Abstract [en]

    The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.

  • 20.
    Fransson, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kratz, Jadel M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Constrained H-Phe-Phe-NH2 Analogues With High Affinity to the Substance P 1-7 Binding Site and With Improved Metabolic Stability and Cell Permeability2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 12, p. 4953-4965Article in journal (Refereed)
    Abstract [en]

    We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP1-7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP1-7 mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability.

  • 21. Ginya, Harumi
    et al.
    Asahina, Junko
    Yoshida, Mamiko
    Segawa, Osamu
    Asano, Tsutomu
    Ikeda, Hideo
    Hatano, Yukiko Miyashita
    Shishido, Madoka
    Johansson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Takahashi, Masaaki
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tajima, Hideji
    Yohda, Masafumi
    Development of the Handy Bio-Strand and its application to genotyping of OPRM1 (A118G)2007In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 367, no 1, p. 79-86Article in journal (Refereed)
    Abstract [en]

    We previously developed a three-dimensional microarray system, the Bio-Strand, which exhibits advantages in automated DNA analysis in combination with our Magtration Technology. In the current study, we have developed a compact system for the Bio-Strand, the Handy Bio-Strand, which consists of several tools for the preparation of Bio-Strand Tip, hybridization, and detection. Using the Handy Bio-Strand, we performed single nucleotide polymorphism (SNP) genotyping of OPRM1 (A118G) by allele-specific oligonucleotide competitive hybridization (ASOCH). DNA fragments containing SNP sites were amplified from genomic DNA by PCR and then were fixed on a microporous nylon thread. Thus, prepared Bio-Strand Tip was hybridized with allele-specific Cy5 probes (<15mer), on which the SNP site was designed to be located in the center. By optimizing the amount of competitors, the selectivity of Cy5 probes increased without a drastic signal decrease. OPRM1 (A118G) genotypes of 23 human genomes prepared from whole blood samples were determined by ASOCH using the Handy Bio-Strand. The results were perfectly consistent with those determined by PCR direct sequencing. ASOCH using the Handy Bio-Strand would be a very simple and reliable method for SNP genotyping for small laboratories and hospitals.

  • 22.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    [(35)S]GTPγS autoradiography for studies of opioid receptor functionality2015In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1230, p. 169-176Article in journal (Refereed)
    Abstract [en]

    The opioid receptors have been an interesting target for the drug industry for decades. These receptors were pharmacologically characterized in the 1970s and several drugs and peptides have emerged over the years. In 2012, the crystal structures were also demonstrated, with new data on the receptor sites, and thus new possibilities will appear. The role of opioids in the brain has attracted considerable interest in several diseases, especially pain and drug dependence. The opioid receptors are G-protein-coupled receptors (GPCR) that are Gi-coupled which make them suitable for studying the receptor functionality. The [(35)S]GTPγS autoradiography assay is a good option that has the benefit of generating both anatomical and functional data in the area of interest. It is based on the first step of the signaling mechanism of GPCRs. When a ligand binds to the receptor GTP will replace GDP on the α-subunit of the G protein, leading to a dissociation of the βγ-subunit. These subunits will start a cascade of second messengers and subsequently a physiological response.

  • 23.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kushnir, Mark M
    ARUP Institute for Clinical and Experimental Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats2013In: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 78, no 12-13, p. 1192-1199Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH) and anabolic androgenic steroids (AAS) are commonly used in sports communities. Several studies have suggested an association between GH and AAS. We have investigated the impact of GH in rats treated with nandrolone decanoate (ND). Male Wistar rats received ND (15 mg/kg) every third day during three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) for ten consecutive days. Plasma samples were collected and peripheral organs (i.e. heart, liver, testis and thymus) were dissected and weighed. Concentration of thirteen endogenous steroids was measured in the rat plasma samples using high specificity LC-MS/MS methods. Seven steroids were detected and quantified, and concentrations of estrone, testosterone, and androstenedione were significantly different among the groups, while concentrations of pregnenolone, DHEA, 17- hydroxyprogesterone and corticosterone were not altered. Administration of rhGH alone altered the plasma steroid distribution, and the results demonstrated significantly increased concentrations of plasma estrone as well as decreased concentrations of testosterone and androstenedione in the ND-treated rats. Administration of rhGH to ND-pretreated rats did not reverse the alteration of the steroid distribution induced by ND. Administration of ND decreased the weight of the thymus, and addition of rhGH did not reverse this reduction. However, rhGH administration induced an enlargement of thymus. Taken together, the plasma steroid profile differed in the four groups, i.e. controls, AAS, rhGH and the combination of AAS and rhGH treatment.

  • 24.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as of the GH receptor, IGF-1, and IGF-2 in rat brain.2014In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 24, no 2-3, p. 60-66Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of AAS administration and a subsequent administration of GH, on the expression of GABAB receptors and important GH mediators in rat brain.

    DESIGN: The aim was to investigate the CNS effects of a high-dose ND, and to study if a low, but physiological relevant, dose of GH could reverse the ND-induced effects. In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala.

    RESULTS: In the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared to the AAS treated group.

    CONCLUSIONS: These results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed.

  • 25.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Recombinant Human Growth Hormone Affects the Density and Functionality of GABAB receptors in the Male Rat Brain2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 97, no 3, p. 203-211Article in journal (Refereed)
    Abstract [en]

    The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABA(B) receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABA(B) receptors in the rat brain. Male Sprague-Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABA(B) stimulated [(35)S]-GTPγS binding using the selective GABA(B) receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABA(B) receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH-induced effects on the GABA(B) receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABA(B) receptors.

  • 26.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nöstl, Anatole
    Högskolan i Gävle.
    Nyberg, Fred J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    GH (Growth hormone) improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats2013In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 216, no 1, p. 31-41Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH) has previously been shown to promote cognitive functions in GH deficient rodents. In this study we report effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for ten consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of insulin-like growth factor 1 (IGF1) were assessed and the gene expression of the GH receptor, Igf1, and Igf2 in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared to controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated to spatial memory, the difference between GH and steroid treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by AAS (anabolic androgenic steroid).

  • 27.
    Grönbladh, Alfhild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The neurobiology and addiction potential of anabolic androgenic steroids and the effects of growth hormone2016In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 126, p. 127-137Article, review/survey (Refereed)
    Abstract [en]

    Anabolic androgenic steroids (AAS) are substances that mimic the hormone testosterone, and primarily act via the androgen receptor. In addition to their physiological effect on muscle tissue and growth, research from the last decade has shown that AAS have a pronounced impact on the central nervous system. A large number of studies have demonstrated that AAS affect the mesolimbic reward system in the brain. However, whether the direct effects of AAS on endorphins, dopamine, serotonin and GABA etc. and on the corresponding and related systems lead to dependence needs to be further elucidated. According to recent studies, the prevalence of AAS dependence among AAS users has been estimated to be approximately 30%, and polysubstance use, of both pharmaceutical drugs and narcotics, within this group is common. The present review primarily discusses AAS in the context of addiction and dependence, and further addresses the issue of using multiple substances, i.e. stimulants and opiates in combination with AAS. In addition, aspects of the treatment of AAS dependence, the connection between AAS abuse and cognition, and AAS-induced neurotoxicity are presented. Currently, performance enhancing drugs are frequently used in combination with AAS. Therefore, a large section on growth hormone and insulin-like growth factor is also included.

  • 28. Guimond, Marie-Odile
    et al.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gallo-Payet, Nicole
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Saralasin and Sarile Are AT2 Receptor Agonists2014In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 10, p. 1129-1132Article in journal (Refereed)
    Abstract [en]

    Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists.

  • 29.
    Hallberg, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    LeGrevés, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neuropeptide processing2005In: Proteases in Biology and Disease, 2005, p. 203-234Chapter in book (Other scientific)
  • 30.
    Hallberg, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Thunell, E
    Kindlundh, AMS
    Nyberg, F
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Anabolic androgenic steroids:A gateway to drug addiction and aggressive behavior2004In: Meth Find Exp Clin Pharmacol, Vol. 26, p. 33-37Article in journal (Other scientific)
  • 31.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Anabola androgena steroider2011In: Beroendemedicin / [ed] Franck, Johan; Nylander, Ingrid, Studentlitteratur AB, 2011, p. 233-240Chapter in book (Other academic)
  • 32.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of Anabolic Androgenic Steroids on Neuropeptide Systems2011In: Mini-Reviews in medical chemistry, ISSN 1389-5575, E-ISSN 1875-5607, Vol. 11, no 5, p. 399-408Article, review/survey (Refereed)
    Abstract [en]

    The abuse of anabolic androgenic steroids (AAS) is relatively widely spread and epidemiological studies in the western countries report a prevalence between 1-5% among males. The impact of these steroids on the strength and muscle mass as well as many of the adverse physical effects that have been observed are well described. Several reports have also revealed severe psychological effects as results of the administration of AAS. Effects such as irritability, aggressiveness, anxiety and depression are reported to be associated with AAS abuse. The mechanistic rationales behind these effects are not well understood. Several systems are likely to be involved, including the monoamine and peptidergic systems. The aim of this review is to highlight the potential role of the neuropeptide systems in the brain with focus on how these systems are affected by repeated administration of AAS.

  • 33.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors2015In: Medicinal research reviews (Print), ISSN 0198-6325, E-ISSN 1098-1128, Vol. 35, no 3, p. 464-519Article, review/survey (Refereed)
    Abstract [en]

    The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.

  • 34.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Targeting the insulin-regulated aminopeptidase/AT(4) receptor for cognitive disorders2009In: Drug News and Perspectives, ISSN 0214-0934, E-ISSN 2013-0139, Vol. 22, no 3, p. 133-139Article, review/survey (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase/AT(4) receptor has recently emerged as a new target for pharmaceutical agents aimed at treating various cognitive disorders such as Alzheimer's disease. There is an unmet need for metabolically stable drug-like angiotensin (Ang) IV analogues that exert actions mimicking the powerful memory-enhancing effects of Ang IV and LVV-hemorphin-7 and can efficiently cross the blood-brain barrier. Such new chemical entities would be attractive as research tools and would allow extensive study of the impact of Ang IV on in vivo physiology in complex animal models. Drug-like Ang IV peptidomimetics are foreseen to serve as potential lead structures for further optimization in drug discovery.

  • 35.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Anabolic-androgenic steroids affect the content of substance P and substance P(1-7) in the rat brain2000In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 21, no 6, p. 845-852Article in journal (Refereed)
    Abstract [en]

    The effects of intramuscular (i.m.) injections of nandrolone decanoate (15 mg/kg/day), an anabolic-androgenic steroid, on the levels of substance P (SP) and on its N-terminal fragment SP(1-7) were examined in the male rat brain by radioimmunoassay. The results demonstrated that the SP immunoreactivity in amygdala, hypothalamus, striatum, and periaqueductal gray was significantly enhanced, whereas the concentration of the N-terminal fragment SP(1-7) was enhanced in the nucleus accumbens and in periaqueductal gray. In the striatum the steroid induced a decrease in the content of SP(1-7). The relevance of these peptides in connection with anabolic-androgenic steroid-induced aggression is discussed.

  • 36.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of chronic nandrolone decanoate administration on the expression of the NK1 receptor density in rat brain as determined by autoradiography2005In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 7, p. 1228-1234Article in journal (Refereed)
    Abstract [en]

    Adult male Sprague–Dawley rats were treated with the anabolic androgenic steroid nandrolone decanoate (15 mg/kg day) or oil vehicle (sterile arachidis oleum) during 14 days. The effect on the densities of the neurokinin NK1 receptor in brain was examined with autoradiography. An overall tendency of attenuation of NK1 receptor density was observed after completed treatment with nandrolone decanoate. The density of the NK1 receptor was found to be significantly lower compared to control animals in the nucleus accumbens core (37% density reduction), in dentate gyrus (26%), in basolateral amygdaloid nucleus (23%), in ventromedial hypothalamic nucleus (36%), in dorsomedial hypothalamic nucleus (43%) and finally in the periaqueductal gray (PAG) (24%). In the cortex region, no structures exhibited any significant reduction of NK1 receptor density. This result provides additional support to the hypothesis that substance P and the NK1 receptor may be involved as important components that participate in mediating physiological responses including the adverse behaviors often associated with chronically administrated anabolic androgenic steroids in human.

  • 37.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Steensland, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The effect of anabolic androgenic steroids on Calcitonin Gene-Related Peptide (CGRP) levels in the rat brain2005In: Pharmacologyonline, Vol. 1, p. 177-195Article in journal (Refereed)
  • 38.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fortfarande oklart om steroider framkallar eget beroende: [Still unclear whether steroids induces addiction on its own].2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 39-40, p. 1736-1739Article in journal (Refereed)
  • 39.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Growth Hormone Receptors in the Brain and their Potential as Therapeutic Targets in Central Nervous System Disorders2012In: The Open Endocrinology Journal, ISSN 1874-2165, E-ISSN 1874-2165, Vol. 6, no Suppl 1, p. 27-33Article, review/survey (Refereed)
    Abstract [en]

    Effects that growth hormone (GH) may exert on brain function have received attention among many researchers over the past two decades. In patients with impaired pituitary production of this hormone replacement therapies have been demonstrated not only to compensate for GH effects in peripheral organs but also to improve several behaviors related to the brain. For instance, available data suggests that subjects treated with GH have experienced significant improvements in concentration, memory, depression, anxiety and fatigue. Also, pituitary-ectomized male rats showing decreased ability in tasks related to learning and memory are seen to improve their performance in these items following GH replacement. The mechanism underlying these beneficial effects of GH has been the subject of studies in many laboratories. An important aspect in this regard is the discovery of specific receptors in various brain regions related to the functional anatomy of several behaviors affected by the hormone. The aim with this article is to review current knowledge on GH receptors in the brain and discuss possible mechanism for the action of the hormone in its ability to affects brain function.

  • 40.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Neuropeptide conversion to bioactive fragments: an important pathway in neuromodulation2003In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 4, no 1, p. 31-44Article in journal (Refereed)
    Abstract [en]

     Biosynthetic pathways for the formation of neuroactive peptides and the processes for their inactivation include several enzymatic steps. In addition to enzymatic processing and degradation, several neuropeptides have been shown to undergo enzymatic conversion to fragments with retained or modified biological activity. This has most clearly been demonstrated for e.g. opioid peptides, tachykinins, calcitonin gene-related peptide (CGRP) as well as for peptides belonging to the renin-angiotensin system. Sometimes the released fragment shares the activity of the parent compound. However, in many cases the conversion reaction is linked to a change in the receptor activation profile, i.e. the generated fragment acts on and stimulates a receptor not recognized by the parent peptide. This review will describe the characteristics of certain neuropeptide fragments having the ability to modify the biological action of the peptide from which they are derived. Focus will be directed to the tachykinins, the opioid peptides, angiotensins as well as to CGRP, bradykinin and nociceptin. The κ opioid receptor selective opioid peptide, dynorphin, recognized for its ability to produce dysphoria, is converted to the δ opioid receptor agonist Leu-enkephalin, with euphoric properties. The tachykinins, typified by substance P (SP), is converted to the bioactive fragment SP(1-7), a heptapeptide mimicking some but opposing other effects of the parent peptide. The bioactive angiotensin II, known to bind to and stimulate the AT-1 and AT-2 receptors, is converted to angiotensin IV (i.e. angiotensin 3-8) with preference for the AT-4 sites or to angiotensin (1-7), not recognized by any of these receptors. Both angiotensin IV and angiotensin (1-7) are biologically active. For example angiotensin (1-7) retains some of the actions ascribed for angiotensin II but is shown to counteract others. Thus, it is obvious that the activity of many neuroactive peptides is modulated by bioactive fragments, which are formed by the action of a variety of peptidases. This phenomenon appears to represent an important regulatory mechanism that modulates many neuropeptide systems but is generally not acknowledged.

  • 41.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    From the Anti-Nociceptive Substance P Metabolite Substance P (1-7) to Small Peptidomimetics2018In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 19, no 11, p. 1038-1048Article, review/survey (Refereed)
    Abstract [en]

    Substance P (SP) is associated with pain and inflammatory processes and is released from terminals of specific sensory nerves. This undecapeptide that mediates its effects through the neurokinin type 1 (NK1) receptor, is rapidly degraded in vivo to smaller fragments. The heptapeptide SP(1-7) with a hitherto unknown receptor, is a major bioactive fragment and displays often opposite actions to those induced by SP. Hence, SP(1-7) elicits anti-nociceptive and anti-hyperalgesic effects. These observations have attracted a substantial interest and in this mini-review the efforts to transform the heptapeptide SP(1-7) into more drug-like small-molecule SP(1-7) peptidomimetics as a potential new class of analgesics are summarized. Structure-activity relationship studies and subsequent amidation of the C-terminal and truncations from the N-terminal of the heptapeptide delivered the bioactive dipeptide amide Gln-Phe-NH2 showing a high affinity at the SP(1-7) binding site. Similarly, endomorphin-2, an endogenous opioid ligand containing a C-terminal carboxamide group, demonstrated a high affinity at the SP(1-7) binding site. Endomorphin-2 subjected to truncations yielded the potent dipeptide amide Phe-Phe-NH2. Structural optimization of the latter furnished more drug-like high affinity ligands and among those a constrained cis-3-phenylpyrrolidine derivative that after peripheral administration produced a significant anti-allodynic effect in a mouse SNI model of neuropathic pain. This SP(1-7) peptidomimetic was as effective as SP(1-7) in alleviating mechanical allodynia in mice. Although, additional structural modifications are needed to achieve compounds exhibiting high/fair bioavailability after oral administration, the examples presented herein demonstrate that the bioactive peptides SP(1-7) and endomorphin-2 can be converted into low molecular weight compounds that are able to mimic the in vivo actions of the heptapeptide SP(1-7).

  • 42.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sumners, Colin
    Univ Florida, Coll Med, Dept Physiol & Funct Genom, Gainesville, FL 32611 USA.;McKnight Brain Inst, Gainesville, FL 32611 USA..
    Steckelings, U. Muscha
    Univ Southern Denmark, Inst Mol Med, Dept Cardiovasc & Renal Res, POB 5230, Odense, Denmark..
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Small-molecule AT2 receptor agonists2018In: Medicinal research reviews (Print), ISSN 0198-6325, E-ISSN 1098-1128, Vol. 38, no 2, p. 602-624Article, review/survey (Refereed)
    Abstract [en]

    The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K-i = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

  • 43.
    Hallberg, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Angiotensin Peptides as AT2 Receptor Agonists2017In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 18, no 8, p. 809-818Article, review/survey (Refereed)
    Abstract [en]

    In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported. This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships (SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews discuss the role of angiotensin peptides as AT2R agonists. Furthermore, to date, there have been no reports focusing on the medicinal chemistry perspective of peptide AT2R agonists. In the present review, reports on linear and conformationally constrained Ang II analogues, with a focus on AT2R selective ligands that are proven to act as agonists at the AT2 receptor are summarized. The impact of truncations and macrocyclizations of Ang II analogues and of incorporation of scaffolds that mimic secondary structures into Ang II related peptides is highlighted. A survey of the efforts to transform the nonselective octapeptide Ang II to more drug-like selective AT2R agonists is presented. The relationship between the structures of the AT2R agonists and their affinity to the AT2R is briefly discussed and common pharmacophore elements of AT2R selective Ang II peptide analogues and selective nonpeptide AT2R agonists are compared.

  • 44.
    Isaksson, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Casselbrant, Anna
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Elebring, Erik
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Lars, Fändriks
    Department of Gastrosurgical Research and Education, Sahlgrenska Academy.
    Direct Stimulation of Angiotensin II Type 2 Receptor Reduce Nitric Oxide Production in Lipopolysaccharide Treated RAW264.7 Mouse MacrophagesManuscript (preprint) (Other academic)
  • 45.
    Isaksson, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Lindman, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wannberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sallander, Jessica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baraldi, Dhaniel
    Department of Pharmacology, Monash University.
    Widdop, Robert
    Department of Pharmacology, Monash University.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Gutierrez de Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode2019In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed)
    Abstract [en]

    We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

  • 46.
    Johansson, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gamma-Hydroxybutyrate (GHB) induces cognitive deficits and affects GABAreceptors and IGF-1 receptors in male rats2014In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 269, p. 164-174Article in journal (Refereed)
    Abstract [en]

    In recent years, the abuse of the club drug Gamma-hydroxy butyric acid (GHB) has become increasingly frequent among adolescents. The drug induces euphoria but can also result in sedation, anaesthesia as well as short-term amnesia. In addition, the abuse of GHB is reported to cause cognitive impairments. The mechanism by which GHB induces impairment in learning and memory has not been fully clarified. The present study investigates the impact on spatial learning and memory using a water maze test in rats treated with GHB. The behavioural data is combined with an autoradiographic analysis of the GABAB and the IGF-1 receptor systems. The results demonstrate that the GHB treated animals display an impaired performance in the water maze test as compared to controls. In addition, significant alterations in GABAB and IGF-1 receptor density as well as GABAB receptor functionality, were observed in several brain regions associated with cognitive functions e.g. hippocampus. To conclude, our findings suggest that GHB treatment can affect spatial learning and memory, and that this outcome at least to some extent is likely to involve both GABAB and IGF-1 receptors.

  • 47.
    Johansson, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Application of in vitro [(35)S]GTPγ-S autoradiography in studies of growth hormone effects on opioid receptors in the male rat brain2013In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 90, p. 100-106Article in journal (Refereed)
    Abstract [en]

    Chronic treatment with opiates may inhibit cell growth and trigger apoptosis. On the contrary, growth hormone (GH) has been demonstrated to stimulate neurogenesis and counteract apoptosis. We recently demonstrated that recombinant human GH (rhGH) may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Thus, GH might be able to prevent the impaired cognitive capabilities that may occur in both humans and other mammals in connection to chronic opiate treatment. In order to explore the mechanism by which GH exerts its beneficial effects we here examined the impact of GH treatment on the levels of delta and mu opioid peptide (DOP and MOP, respectively) receptors in the male rat brain. The rats were treated with rhGH (Genotropin(®)) at two different doses (0.07 and 0.7IU/kg), twice daily, during 7 days. Following decapitation, the levels of DOP and MOP receptor functionality were determined using [(35)S]GTPγS autoradiography. The results demonstrate that rhGH affects the levels of the MOP receptor functionality in certain areas of the brain. These alterations were seen in e.g. amygdala and thalamus, i.e. regions that recently have been implicated in learning and memory. The activity level of DOP receptors was not affected. Thus, the data support that the beneficial effect of GH on counteracting apoptosis might involve a direct or indirect effect on the MOP but not the DOP receptor.

  • 48.
    Johansson, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The effect on opioid peptides in the rat brain, after chronic treatment with the anabolic androgenic steroid, nandrolone decanoate2000In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 51, no 5, p. 413-418Article in journal (Refereed)
    Abstract [en]

    In recent years, an increase in abuse of anabolic androgenic steroids (AAS) has been seen among individuals not directly connected to sports. Clinical evidence suggests that abuse of these steroids may result in profound changes in personality, expressed by depressive symptoms, irritability and increased aggression. It is still unknown whether these alterations are related to changes in any particular transmitter system or whether they are persistent or reversible. In this study we focused on AAS effect on the endogenous dynorphin and enkephalin system in the brain. Male rats were given intramuscular injections of the AAS nandrolone decanoate (15 mg/kg), once daily for 2 weeks. The levels of the opioid peptide immunoreactivities (ir) were assessed by radioimmunoassay in two groups immediately after the treatment and in two other groups after additional 3 weeks without any drug treatment (recovery period). The result indicates that chronic AAS treatment increased the activity in the dynorphin B- and Met-enkephalin-Arg6Phe7-ir in the hypothalamus, striatum and periaqueductal gray (PAG) compared to controls. In addition, the steroid induced an imbalance between the dynorphin and the enkephalin opioid system in the nucleus accumbens, hypothalamus and PAG. This imbalance remained after the recovery period. Since increased peptide activity was found in brain regions regulating emotions, dependence, defensive reactions and aggression, it was suggested that the actual endogenous opioid systems are involved in previously reported AAS-induced changes in these behaviours.

  • 49.
    Jonsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Haramaki, Yutaka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Skogh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brolin, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nordvall, Gunnar
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice2015In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 298, p. 112-119Article in journal (Refereed)
    Abstract [en]

    Previous results have shown that the substance P (SP) N-terminal fragment SP1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1–7. The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1–7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.

  • 50.
    Kindlundh, Anna MS
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Monazzam, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Blomqvist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dopaminergic effects after chronic treatment with nandrolone visualized in rat brain by positron emission tomography2002In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 26, no 7-8, p. 1303-1308Article in journal (Refereed)
    Abstract [en]

    Anabolic-androgenic steroids (AAS) have recently been shown to induce neurochemical alterations in areas of the male rat CNS related to behavioural changes that have been observed among AAS misusers. In the present study, positron emission tomography (PET) is suggested as a suitable in vivo method in order to visualize the density of the dopamine transporter ([11C]-FE-beta-CIT) as well as the dopamine D1-like ([11C]-(+)-SCH23390) and the D2-like receptors ([11C]-raclopride) in the male rat brain. Chronic treatment with the AAS nandrolone decanoate (15 mg/kg/day for 14 days) caused an up-regulation of the binding potential of the dopamine transporter in the striatum.

12 1 - 50 of 88
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