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  • 1.
    Andappan, Murugaiah M. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mahalingam, A. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wan, Yiqian
    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.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Guimond, Marie-Odile
    Joshi, Advait
    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.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 5, p. 2265-2278Article in journal (Refereed)
    Abstract [en]

    A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.

  • 2.
    Behrends, Malte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wieckowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Guimond, Marie-Odile
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gallo-Payet, Nicole
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    N-Aryl Isoleucine Derivatives as Angiotensin II AT(2) Receptor Ligands2014In: ChemistryOpen, ISSN 2191-1363, Vol. 3, no 2, p. 65-75Article in journal (Refereed)
    Abstract [en]

    A novel series of ligands for the recombinant human AT(2) receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)(6)] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with K-i values in the low micromolar range versus the recombinant human AT(2) receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs.

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  • 3.
    Gallo-Payet, Nicole
    et al.
    Service of Endocrinology, Department of Medicine, University of Sherbrooke, Canada.
    Guimond, Marie-Odile
    Service of Endocrinology, Department of Medicine, University of Sherbrooke, Canada.
    Bilodeau, Lyne
    Service of Endocrinology, Department of Medicine, University of Sherbrooke, Canada.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    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 II, a neuropeptide at frontier between endocrinology and neuroscience:  is there a link between the angiotensin II type 2 receptor andAlzheimer’s disease?2011In: Frontiers in Endocrinology, ISSN 1664-2392, Vol. 2, p. Article 17-Article in journal (Refereed)
    Abstract [en]

    Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer’s disease (AD). Angiotensin II (Ang II) is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type 1 receptor (AT1R) and the type 2 receptor (AT2R). Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs) attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by non-peptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in AD and other neurological cognitive disorders.

  • 4. Gallo-Payet, Nicole
    et al.
    Shum, Michael
    Baillargeon, Jean-Patrice
    Langlois, Marie-France
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    C. Carpentier, Andre
    AT2 Receptor Agonists: Exploiting the Beneficial Arm of Ang II Signaling2012In: current hypertension reviews, ISSN 1573-4021, Vol. 8, no 1, p. 47-59Article, review/survey (Refereed)
    Abstract [en]

    In the classical view, the hormone angiotensin II (Ang II) mediates its action via two major receptors, namely the Ang II type-1 receptor (AT1R) and the type-2 receptor (AT2R). Several recent reviews implicate the renin-angiotensin system (RAS) in various aspects of adipose tissue physiology and dysfunction. Research on AT2R has long been hampered by at least three potential challenges, (i) the low expression level of the AT2R in the adult, (ii) the atypical signaling pathways of AT2R and (iii) the absence of appropriate selective ligands. Indeed, apart a few exceptions, the role of the AT2R was in fact revealed by the results of simultaneous treatment with Ang II and AT1R blockers or in AT2Rdeficient mice. The first aim of this review is to summarize current paradigms concerning the role of the AT2R in adipocyte differentiation and in metabolic disorders related to insulin resistance and type 2 diabetes. Secondly, we will highlight the potential utility of selective AT2R agonists in clarifying potential roles of the AT2R in adipocyte physiology. We summarized our findings using a selective and high affinity nonpeptide ligand of the AT2R and demonstrate that AT2R is involved in adipocyte differentiation and may improve insulin sensitivity in a model of insulin resistance, in addition to increase vasodilation and reduce inflammation in adipose tissue. Thus the recent development of orally active, selective AT2R agonists should facilitate efforts to elucidate the distinct roles of the AT2R in physiology, including adipocyte physiology.

  • 5.
    Georgsson, Jennie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Beaudry, Hélène
    Plouffe, Bianca
    Lindeberg, Gunnar
    Botros, Milad
    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.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity2006In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 17, p. 5963-5972Article in journal (Refereed)
    Abstract [en]

    Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.

  • 6. 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.

  • 7.
    Guimond, Marie-Odile
    et al.
    Univ Sherbrooke, Fac Med, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada; Univ Sherbrooke, Fac Med, Dept Physiol & Biophys, Sherbrooke, PQ J1H 5N4, Canada.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Altermann, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gallo-Payet, Nicole
    Univ Sherbrooke, Fac Med, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada; Univ Sherbrooke, Fac Med, Dept Physiol & Biophys, Sherbrooke, PQ J1H 5N4, Canada.
    Comparative functional properties of two structurally similar selective nonpeptide drug-like ligands for the angiotensin II type-2 (AT2) receptor. Effects on neurite outgrowth in NG108-15 cells2012In: European Journal of Pharmacology - Molecular Pharmacology Section, ISSN 0922-4106, E-ISSN 1872-8251, Vol. 699, no 1-3, p. 160-171Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence that angiotensin II (Ang II), through binding to the type 2 (AT(2)) receptor may have beneficial effects in various physiological and pathological situations. However, specific action presumably mediated by the angiotensin AT(2) receptor has been hampered by the absence of appropriate selective ligands. The aim of this study was to compare the biological properties of two related and selective drug-like nonpeptide AT(2) ligands, namely an agonist called M024 (also known as Compound 21) and a new ligand, presumably an antagonist, C38/M132, (originally called C38). Properties of the compounds were investigated in NG108-15 cells expressing angiotensin AT(2) receptor and known to develop neurite outgrowth upon Ang II stimulation. NG108-15 cells stimulated for three days with C21/M024 (0.1 or 100 nM) exhibited the same neurite outgrowth as cells stimulated with Ang II (100 nM) while co-incubation of Ang II or C21/M024 with C38/M132 (10 or 100 nM) inhibited their effects, similarly to the angiotensin AT(2) receptor antagonist, PD123319 (10 mu M). As Ang II, C21/M024 induced a Rap1-dependent activation of p42/p44(mapk) whereas preincubation of cells with C38/M132 inhibited p42/p44(mapk) and Rap1 activation induced by Ang II. Three-day treatment with C21/M024 or Ang II decreased cell number in culture, an effect that was rescued by preincubation with C38/M132. Taken together, these results indicate that the nonpeptide ligand C21/M024 is a potent angiotensin AT(2) receptor agonist while C38/M132 acts as an antagonist. These selective nonpeptide angiotensin AT(2) ligands may represent unique and long-awaited tools for the pursuit of in vivo studies.

  • 8.
    Gullbo, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Tullberg, Marcus
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Luthman, Kristina
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester): Comparison with its m-L-sarcolysin analogue P22003In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 2, no 12, p. 1331-1339Article in journal (Refereed)
    Abstract [en]

    Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.

  • 9.
    Mahalingam, A. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wan, Yiqian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Murugaiah, A. M. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Plouffe, Bianca
    Botros, Milad
    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, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gallo-Payet, Nicole
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 12, p. 4570-4590Article in journal (Refereed)
    Abstract [en]

    Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT(2) selective agonist.

  • 10.
    Sallander, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    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. Uppsala Univ, Biomed Ctr, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden..
    Gutierrez de Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Structural determinants of subtype selectivity and functional activity of angiotensin II receptors2016In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 26, no 4, p. 1355-1359Article in journal (Refereed)
    Abstract [en]

    Agonists of the angiotensin II receptor type 2 (AT(2)), a G-protein coupled receptor, promote tissue protective effects in cardiovascular and renal diseases, while antagonists reduce neuropathic pain. We here report detailed molecular models that explain the AT(2) receptor selectivity of our recent series of non-peptide ligands. In addition, minor structural changes of these ligands that provoke different functional activity are rationalized at a molecular level, and related to the selectivity for the different receptor conformations. These findings should pave the way to structure based drug discovery of AT(2) receptor ligands.

  • 11. Shum, Michael
    et al.
    Pinard, Sandra
    Guimond, Marie-Odile
    Labbe, Sebastien M.
    Roberge, Claude
    Baillargeon, Jean-Patrice
    Langlois, Marie-France
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    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.
    Carpentier, Andre C.
    Gallo-Payet, Nicole
    Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats2013In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 304, no 2, p. E197-E210Article in journal (Refereed)
    Abstract [en]

    Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. Am J Physiol Endocrinol Metab 304: E197-E210, 2013. First published November 13, 2012; doi:10.1152/ajpendo.00149.2012.-This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPA gamma expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPAR gamma remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.

  • 12.
    Steckelings, U. Muscha
    et al.
    Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany.
    Larhed, Mats
    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.
    Widdop, Robert E.
    Department of Pharmacology, Monash University, Clayton, Australia.
    Jones, Emma S.
    Department of Pharmacology, Monash University, Clayton, Australia.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Namsolleck, Pawel
    Center for Cardiovascular Research, Charité-Universitätsmedizin, Berlin, Germany.
    Dahlöf, Björn
    Sahlgrenska University Hospital/Östra, Sweden.
    Unger, Thomas
    Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany.
    Non-peptide AT2-receptor agonists2011In: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 11, no 2, p. 187-192Article in journal (Refereed)
    Abstract [en]

    The renin-angiotensin-system harbours two main receptor subtypes binding angiotensin II which are the AT1-receptor and the AT2-receptor. While the AT1-receptor has been a drug target in cardiovascular disease for many years, the AT2-receptor was only a subject of academic interest. This has changed with the design and synthesis of a first non-peptide, orally active AT2-receptor agonist, compound 21 (C21). First data using 021 revealed tissue protective effects and functional improvement after myocardial infarction and in hypertension-induced end organ damage, notably in a blood-pressure independent way. In all of these models, AT2-receptor mediated anti-inflammation seemed an important underlying mechanism. 021 is awaited to enter a phase I clinical study in 2011.

  • 13.
    Veron, Jean-Baptiste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Joshi, Advait
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    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.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis and evaluation of isoleucine derived angiotensin II AT(2) receptor ligands2014In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 24, no 2, p. 476-479Article in journal (Refereed)
    Abstract [en]

    Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT(2)R ligand, were designed, synthesized and evaluated for their affinity to the AT(2)R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, K-i = 8.5 mu M) was over 12-times more potent than the lead compound 2.

  • 14.
    Wallinder, Charlotta
    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.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Guimond, Marie-Odile
    Beaudry, Hélène
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selective angiotensin II AT2 receptor agonists: Benzamide structure–activity relationships2008In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 14, p. 6841-6849Article in journal (Refereed)
    Abstract [en]

    In the investigation of the structure–activity relationship of nonpeptide AT2 receptor agonists, a series of substituted benzamide analogues of the selective nonpeptide AT2 receptor agonist M024 have been synthesised. In a second series, the biphenyl scaffold was compared to the thienylphenyl scaffold and the impact of the isobutyl substituent and its position on AT1/AT2 receptor selectivity was also investigated. Both series included several compounds with high affinity and selectivity for the AT2 receptor. Three of the compounds were also proven to function as agonists at the AT2 receptor, as deduced from a neurite outgrowth assay, conducted in NG108-15 cells.

  • 15.
    Wallinder, Charlotta
    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.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Guimond, Marie-Odile
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gallo-Payet, Nicole
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands2015In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 6, no 2, p. 178-182Article in journal (Refereed)
    Abstract [en]

    Migration of the methylene imidazole side chain in the first reported selective drug-like AT, receptor agonist C21/M024 (1) delivered the AT, receptor antagonist C38/M132 (2). We now report that the AT, receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.

  • 16.
    Wallinder, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Sundholm, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Guimond, Marie-Odile
    Univ Sherbrooke, Fac Med & Hlth Sci, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada.
    Yahiaoui, Samir
    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.
    Gallo-Payet, Nicole
    Univ Sherbrooke, Fac Med & Hlth Sci, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    High affinity rigidified AT(2) receptor ligands with indane scaffolds2019In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 12, p. 2146-2160Article in journal (Refereed)
    Abstract [en]

    Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.

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  • 17.
    Wan, Yigian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Johansson, Berndt
    Holm, Mathias
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pettersson, Anders
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fändriks, Lars
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    First Reported Nonpeptide AT1 Receptor Agonist (L-162,313) Acts as an AT2 Receptor Agonist in Vivo2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 6, p. 1536-1546Article in journal (Refereed)
    Abstract [en]

    In this investigation, it is demonstrated that the first nonpeptide AT1 receptor agonist L-162,313 (1), disclosed in 1994, also acts as an agonist at the AT2 receptor. In anesthetized rats, administration of compound 1 intravenously or locally in the duodenum increased duodenal mucosal alkaline secretion, effects that were sensitive to the selective AT2 receptor antagonist PD-123,319. The data strongly suggest that 1 is an AT2 receptor agonist in vivo. To the best of our knowledge, this substance is the first nonpeptidic low-molecular weight compound with an agonistic effect mediated through the AT2 receptor.

  • 18.
    Wan, Yigian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Plouffe, Bianca
    Beaudry, Hélène
    Mahalingam, A. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wu, Xiongyu
    Johansson, Berndt
    Holm, Mathias
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Pettersson, Anders
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fändriks, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design, Synthesis, and Biological Evaluation of the First Selective Nonpeptide AT2 Receptor Agonist2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 24, p. 5995-6008Article in journal (Refereed)
    Abstract [en]

    The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

  • 19.
    Wannberg, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unlusoy, Meltem
    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.
    One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates2013In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 8, p. 4184-4189Article in journal (Refereed)
    Abstract [en]

    A convenient procedure for converting aryl alcohols to aryl fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to good one-pot, two-step yields were achieved by this nonaflation and microwave-assisted, palladium-catalyzed fluorination sequence. The reductive elimination step was investigated by DFT calculations to compare fluorination with chlorination, proving a larger thermodynamic driving force for the aryl fluoride product. Finally, a key aryl fluoride intermediate for the synthesis of a potent HCV NS3 protease inhibitor was smoothly prepared with the novel protocol.

  • 20.
    Åberg, Ola
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Stevens, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. ORGFARM.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hall, Håkan
    Monazzam, Azita
    Uppsala Imanet, GE Healthcare.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand2010In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 53, no 10, p. 616-624Article in journal (Refereed)
    Abstract [en]

    Three C-11-radiolabelled high-affinity nonpeptide AT(2) receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [C-11] carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [C-11] carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[C-11] carbamoyl)phenyl]-5-isobutylthiophene-2-sulphonamide [C-11]4d was obtained in 36% decay-corrected radiochemical yield (from [C-11] carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq.mu mol(-1). The N-isopropyl-[C-11] carbamoyl-analogue [C-11]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT(2) receptors in living subjects.

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