Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor
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2017, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Several selective agonists for MC1R, MC3R, MC4R and MC5R were also created [42–46] [47]. Many synthetic small molecular agonists were developed due to the importance of the MCRs in the regulation of human physiology, especially for hMC4R [44,48–56]. These synthetic compounds have different chemical structures compared to that of MSH but they are selective for MC4R.
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2017, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :This compound blocked α-MSH stimulated cAMP production with a IC50 value of 93 nM. Interestingly, the cis-isomers of the pyrrolidine substitution were found to impart higher binding affinity, in contrast to the trans-isomers previously reported when the pyrrolidine nitrogen is in a different location (4 versus 1 and 2, Fig. 3) [147,148]. The group at Neurocrine also investigated a series of piperazinebenzylalcohols and related ketones and amine analogs without the pyrrolidine ring (5, Fig. 3) [150].
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2012, Drug Discovery TodayCitation Excerpt :MCRs having multiple roles such as energy homeostasis and sexual behavior have been targeted over the past decade [12]. In the discovery program for a selective MC4 receptor agonist, a series of pyrrolidine-based compounds having different stereocenters was reported [13,14]. One kind of compound having (3S, 4R) stereochemistry in the pyrrolidine scaffold (7; Fig. 2) delivered an agonistic response whereas that with opposite stereochemistry (8; Fig. 2) gave an antagonistic response.
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2011, Bioorganic and Medicinal ChemistryCitation Excerpt :Further SAR elucidation of the currently identified nAChR ligands can not only lead to improvement of binding affinity and modulation of nAChR subtype selectivity, but also to altered functional activity of the ligands. In previous studies, for example, analogues of the nAChR agonist epibatidine have been synthesized with antagonistic activity on nAChRs,34 and subtle chemical changes have been shown to change the functional activity of ligands for other receptors as well.35–38 It is noted that α7 antagonists are useful not only as molecular tools to investigate the pharmacology of the receptor, but also as drug candidates with anti-cancer effects.39
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Present address: Department of Medicinal Chemistry, Tanabe Research Laboratories, USA, Inc., 4540 Towne Centre Ct., San Diego, CA 92121, USA.
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Present address: Vertex Pharmaceuticals, Inc., 11010 Torreyana Road, San Diego, CA 92121, USA.