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Wallinder, Charlotta
Publications (10 of 19) Show all publications
Sallander, J., Wallinder, C., Hallberg, A., Åqvist, J. & Gutierrez de Teran, H. (2016). Structural determinants of subtype selectivity and functional activity of angiotensin II receptors. Bioorganic & Medicinal Chemistry Letters, 26(4), 1355-1359
Open this publication in new window or tab >>Structural determinants of subtype selectivity and functional activity of angiotensin II receptors
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2016 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 26, no 4, p. 1355-1359Article in journal (Refereed) Published
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.

Keywords
Angiotensin receptors, Conformational selection, Molecular docking, Homology modeling, Ligand interaction
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-279553 (URN)10.1016/j.bmcl.2015.10.084 (DOI)000369377700052 ()26810314 (PubMedID)
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2018-01-10Bibliographically approved
Wallinder, C., Sköld, C., Botros, M., Guimond, M.-O., Hallberg, M., Gallo-Payet, N., . . . Alterman, M. (2015). Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands [Letter to the editor]. ACS Medicinal Chemistry Letters, 6(2), 178-182
Open this publication in new window or tab >>Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands
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2015 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 6, no 2, p. 178-182Article in journal, Letter (Refereed) Published
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.

National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-97465 (URN)10.1021/ml500427r (DOI)000349652000013 ()25699147 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2018-01-13Bibliographically approved
Behrends, M., Wallinder, C., Wieckowska, A., Guimond, M.-O., Hallberg, A., Gallo-Payet, N. & Larhed, M. (2014). N-Aryl Isoleucine Derivatives as Angiotensin II AT(2) Receptor Ligands. ChemistryOpen, 3(2), 65-75
Open this publication in new window or tab >>N-Aryl Isoleucine Derivatives as Angiotensin II AT(2) Receptor Ligands
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2014 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 3, no 2, p. 65-75Article in journal (Refereed) Published
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.

Keywords
aminocarbonylation, AT(2) receptor, medicinal chemistry, palladium catalysis, peptide mimics
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-225073 (URN)10.1002/open.201300040 (DOI)000334680800004 ()
Available from: 2014-06-19 Created: 2014-05-27 Last updated: 2018-01-11Bibliographically approved
Guimond, M.-O., Hallberg, M., Gallo-Payet, N. & Wallinder, C. (2014). Saralasin and Sarile Are AT2 Receptor Agonists. ACS Medicinal Chemistry Letters, 5(10), 1129-1132
Open this publication in new window or tab >>Saralasin and Sarile Are AT2 Receptor Agonists
2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 10, p. 1129-1132Article in journal (Refereed) Published
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.

National Category
Pharmaceutical Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-235670 (URN)10.1021/ml500278g (DOI)000343016700012 ()25313325 (PubMedID)
Available from: 2014-11-07 Created: 2014-11-07 Last updated: 2018-01-11Bibliographically approved
Veron, J.-B., Joshi, A., Wallinder, C., Larhed, M. & Odell, L. R. (2014). Synthesis and evaluation of isoleucine derived angiotensin II AT(2) receptor ligands. Bioorganic & Medicinal Chemistry Letters, 24(2), 476-479
Open this publication in new window or tab >>Synthesis and evaluation of isoleucine derived angiotensin II AT(2) receptor ligands
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2014 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 24, no 2, p. 476-479Article in journal (Refereed) Published
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.

National Category
Natural Sciences Basic Medicine
Identifiers
urn:nbn:se:uu:diva-217652 (URN)10.1016/j.bmcl.2013.12.040 (DOI)000329430600013 ()
Available from: 2014-02-12 Created: 2014-02-04 Last updated: 2018-01-11Bibliographically approved
Shum, M., Pinard, S., Guimond, M.-O., Labbe, S. M., Roberge, C., Baillargeon, J.-P., . . . Gallo-Payet, N. (2013). Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. American Journal of Physiology. Endocrinology and Metabolism, 304(2), E197-E210
Open this publication in new window or tab >>Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats
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2013 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 304, no 2, p. E197-E210Article in journal (Refereed) Published
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.

Keywords
angiotensin type 2 receptor, adipocyte, differentiation, PPAR gamma, high-fat/high-fructose diet
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-194751 (URN)10.1152/ajpendo.00149.2012 (DOI)000313614700009 ()
Available from: 2013-02-19 Created: 2013-02-19 Last updated: 2017-12-06Bibliographically approved
Wannberg, J., Wallinder, C., Unlusoy, M., Sköld, C. & Larhed, M. (2013). One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates. Journal of Organic Chemistry, 78(8), 4184-4189
Open this publication in new window or tab >>One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates
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2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 8, p. 4184-4189Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-203361 (URN)10.1021/jo400255m (DOI)000319708300024 ()
Available from: 2013-07-09 Created: 2013-07-09 Last updated: 2017-12-06Bibliographically approved
Gallo-Payet, N., Shum, M., Baillargeon, J.-P., Langlois, M.-F., Wallinder, C., Alterman, M., . . . C. Carpentier, A. (2012). AT2 Receptor Agonists: Exploiting the Beneficial Arm of Ang II Signaling. current hypertension reviews, 8(1), 47-59
Open this publication in new window or tab >>AT2 Receptor Agonists: Exploiting the Beneficial Arm of Ang II Signaling
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2012 (English)In: current hypertension reviews, ISSN 1573-4021, Vol. 8, no 1, p. 47-59Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
bentham science publishers, 2012
Keywords
Angiotensin II, angiotensin type 2 receptor, angiotensin type 1 receptor, adipocyte, differentiation, insulin resistance, adipocytes, AT1R blockade, proliferator-activated receptor
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-191000 (URN)10.2174/157340212800504990 (DOI)
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2018-01-11Bibliographically approved
Guimond, M.-O., Wallinder, C., Altermann, M., Hallberg, A. & Gallo-Payet, N. (2012). 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 cells. European Journal of Pharmacology - Molecular Pharmacology Section, 699(1-3), 160-171
Open this publication in new window or tab >>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 cells
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2012 (English)In: 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) Published
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.

Keywords
Angiotensin II, AT(2) receptor agonist, AT(2) receptor antagonist, Neurite outgrowth, MAPK activation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-190970 (URN)10.1016/j.ejphar.2012.11.032 (DOI)000314659600022 ()
Funder
Swedish Research Council
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2018-01-11Bibliographically approved
Andappan, M. M. S., Wu, X., Wallinder, C., Mahalingam, A. K., Wan, Y., Sköld, C., . . . Alterman, M. (2012). From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists. Journal of Medicinal Chemistry, 55(5), 2265-2278
Open this publication in new window or tab >>From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 5, p. 2265-2278Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-172030 (URN)10.1021/jm2015099 (DOI)000301170000040 ()
Available from: 2012-04-02 Created: 2012-04-01 Last updated: 2017-12-07Bibliographically approved
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