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Hallberg, M
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Publications (10 of 88) Show all publications
Isaksson, R., Lindman, J., Wannberg, J., Sallander, J., Backlund, M., Baraldi, D., . . . Larhed, M. (2019). A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode. ChemistryOpen, 8(1), 114-125
Open this publication in new window or tab >>A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
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2019 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed) Published
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.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-377050 (URN)10.1002/open.201800282 (DOI)000457433000017 ()30697513 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC)Swedish Research Council
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-04-04Bibliographically approved
Zelleroth, S., Nylander, E., Nyberg, F., Grönbladh, A. & Hallberg, M. (2019). Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures. Neuroscience, 397, 172-183
Open this publication in new window or tab >>Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures
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2019 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 397, p. 172-183Article in journal (Refereed) Published
Abstract [en]

The use of anabolic androgenic steroids (AASs) among non-athletes is a public health-problem, as abusers underestimate the negative effects associated with these drugs. The present study investigated the toxic effects of testosterone, nandrolone, stanozolol, and trenbolone, and aimed to understand how AAS abuse affects the brain. Mixed cortical cultures from embryonic rats were grown in vitro for 7 days and thereafter treated with increasing concentrations of AASs for 24 h (single-dose) or 3 days (repeated exposure). Cells were co-treated with the androgen-receptor (AR) antagonist flutamide, to determine whether the potential adverse effects observed were mediated by the AR. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase (LDH) release, and caspase-3/7 activity. Nandrolone, unlike the other AASs studied, indicated an effect on mitochondrial activity after 24 h. Furthermore, single-dose exposure with testosterone, nandrolone and trenbolone increased LDH release, while no effect was detected with stanozolol. However, all of the four steroids negatively affected mitochondrial function and resulted in LDH release after repeated exposure. Testosterone, nandrolone, and trenbolone caused their toxic effects by induction of apoptosis, unlike stanozolol that seemed to induce necrosis. Flutamide almost completely prevented AAS-induced toxicity by maintaining mitochondrial function, cellular integrity, and inhibition of apoptosis. Overall, we found that supra-physiological concentrations of AASs induce cell death in mixed primary cortical cultures, but to different extents, and possibly through various mechanisms. The data presented herein suggest that the molecular interactions of the AASs with the AR are primarily responsible for the toxic outcomes observed.

Keywords
mitochondrial function membrane integrity cell death androgen-receptor flutamide
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-370111 (URN)10.1016/j.neuroscience.2018.11.035 (DOI)000454922800016 ()30500611 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain Foundation
Note

Även finansierat av Kjell och Märta Beijers stiftelse

Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-28Bibliographically approved
Wannberg, J., Isaksson, R., Bremberg, U., Backlund, M., Sävmarker, J., Hallberg, M. & Larhed, M. (2018). A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes. Bioorganic & Medicinal Chemistry Letters, 28(3), 519-522
Open this publication in new window or tab >>A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed) Published
Abstract [en]

A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
AT(2)R antagonists, Angiotensin II type 2 receptor antagonists, Liver microsomes, Sulfonyl carbamates, Transesterification
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343592 (URN)10.1016/j.bmcl.2017.11.042 (DOI)000424285600053 ()29279275 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2019-04-04Bibliographically approved
Skogh, A., Lesniak, A., Sköld, C., Karlgren, M., Gaugaz, F. Z., Svensson, R., . . . Johansson, A. (2018). An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice. Bioorganic & Medicinal Chemistry Letters, 28(14), 2446-2450
Open this publication in new window or tab >>An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 14, p. 2446-2450Article in journal (Refereed) Published
Abstract [en]

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343682 (URN)10.1016/j.bmcl.2018.06.009 (DOI)000438467200020 ()29929882 (PubMedID)
Funder
Swedish Research Council, 9459
Note

Title in dissertation reference list: An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability

Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-24Bibliographically approved
Brolin, E., Zelleroth, S., Jonsson, A., Hallberg, M., Grönbladh, A. & Nyberg, F. (2018). Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat. Pharmacology, Biochemistry and Behavior, 167, 1-8
Open this publication in new window or tab >>Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
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2018 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 167, p. 1-8Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Morphine, Morris water maze (MWM), Mini-osmotic pumps, Memory, Insulin-like growth factor-1 (IGF-1), N-methyl-D-aspartate (NMDA), Rats
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-352711 (URN)10.1016/j.pbb.2018.01.007 (DOI)000430033600001 ()29421366 (PubMedID)
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2019-05-28
Hallberg, M. & Sandström, A. (2018). From the Anti-Nociceptive Substance P Metabolite Substance P (1-7) to Small Peptidomimetics. Current protein and peptide science, 19(11), 1038-1048
Open this publication in new window or tab >>From the Anti-Nociceptive Substance P Metabolite Substance P (1-7) to Small Peptidomimetics
2018 (English)In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 19, no 11, p. 1038-1048Article, review/survey (Refereed) Published
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).

Keywords
Substance P, substance P (1-7), endomorphin-2, peptidomimetics, bioactive fragments, neuropathic pain, allodynia
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-369228 (URN)10.2174/1389203719666180508122019 (DOI)000445653000001 ()29745331 (PubMedID)
Funder
The Swedish Brain Foundation
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Hallberg, M., Sumners, C., Steckelings, U. M. & Hallberg, A. (2018). Small-molecule AT2 receptor agonists. Medicinal research reviews (Print), 38(2), 602-624
Open this publication in new window or tab >>Small-molecule AT2 receptor agonists
2018 (English)In: Medicinal research reviews (Print), ISSN 0198-6325, E-ISSN 1098-1128, Vol. 38, no 2, p. 602-624Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
angiotensin II, AT2 receptor, peptidomimetics, renin-angiotensin system
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-348314 (URN)10.1002/med.21449 (DOI)000425027400006 ()28609561 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-04-25 Created: 2018-04-25 Last updated: 2018-04-25Bibliographically approved
Reddy Vanga, S., Sävmarker, J., Ng, L., Larhed, M., Hallberg, M., Åqvist, J., . . . Gutiérrez-de-Terán, H. (2018). Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides. ACS OMEGA, 3(4), 4509-4521
Open this publication in new window or tab >>Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides
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2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed) Published
Abstract [en]

The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Biochemistry and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-358572 (URN)10.1021/acsomega.8b00595 (DOI)000434352800025 ()30023895 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved
Nylander, E., Zelleroth, S., Nyberg, F., Grönbladh, A. & Hallberg, M. (2018). The Protective and Restorative Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Methadone-Induced Toxicity In Vitro. International Journal of Molecular Sciences, 19(11), 1-16, Article ID ijms-387278.
Open this publication in new window or tab >>The Protective and Restorative Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Methadone-Induced Toxicity In Vitro
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2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 11, p. 1-16, article id ijms-387278Article in journal (Refereed) Published
Abstract [en]

Evidence to date suggests that opioids such as methadone may be associated with cognitive impairment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are suggested to be neuroprotective and procognitive in the brain and may therefore counteract these effects. This study aims to explore the protective and restorative effects of GH and IGF-1 in methadone-treated cell cultures. Primary cortical cell cultures were harvested from rat fetuses and grown for seven days in vitro. To examine the protective effects, methadone was co-treated with or without GH or IGF-1 for three consecutive days. To examine the restorative effects, methadone was added for the first 24 h, washed, and later treated with GH or IGF-1 for 48 h. At the end of each experiment, mitochondrial function and membrane integrity were evaluated. The results revealed that GH had protective effects in the membrane integrity assay and that both GH and IGF-1 effectively recovered mitochondrial function and membrane integrity in cells pretreated with methadone. The overall conclusion of the present study is that GH, but not IGF-1, protects primary cortical cells against methadone-induced toxicity, and that both GH and IGF-1 have a restorative effect on cells pretreated with methadone.

Keywords
growth hormone; insulin-like growth factor-1; neuroprotection; neurorecovery; cognition; primary cell cultures; methadone; opioids
National Category
Basic Medicine Cell and Molecular Biology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-369995 (URN)10.3390/ijms19113627 (DOI)000451528500343 ()30453639 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain Foundation
Note

Även finansierat av Kjell och Märta Beijer stiftelsen.

Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2019-01-08Bibliographically approved
Hallberg, M., Sävmarker, J. & Hallberg, A. (2017). Angiotensin Peptides as AT2 Receptor Agonists. Current protein and peptide science, 18(8), 809-818
Open this publication in new window or tab >>Angiotensin Peptides as AT2 Receptor Agonists
2017 (English)In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 18, no 8, p. 809-818Article, review/survey (Refereed) Published
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.

Keywords
Angiotensin II, AT2 receptor agonist, peptide, peptidemimetic, secondary structure mimetic, bioactive conformation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-335828 (URN)10.2174/1389203718666170203150344 (DOI)000405303000003 ()28164758 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2017-12-15Bibliographically approved
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