Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists.

[摘要]：Differentiation of the physiol. role of the melanocortin receptor 5 MC5R from that of other melanocortin receptors will require development of high affinity and selective antagonists. To date, a few synthetic antagonist ligands active at hMC5 receptor are available, but most do not have appreciable selectivity. With the aim to gain more potent and selective antagonists for the MC5R ligands, the authors have designed, synthesized, and pharmacol. characterized a series of alkylthioaryl-bridged macrocyclic peptide analogs derived from MT-II and SHU9119. These 20-membered macrocycles were synthesized by a tandem combination using solid-phase peptide synthesis and microwave-assisted reactions. Biol. assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogs, compds., 9, 4, and 7, are selective antagonists at the hMC5 receptor. In particular, compd. 9 (PG-20N) is a selective and competitive hMC5R antagonist, with IC50 of 130 ?11 nM, and a pA2 value of 8.3, and represents an important tool for further show potent and selective allosteric inhibition at hMC5R with IC50 values of 38 ?3 nM and 58 ?6 nM, resp. Compd. 9 will be used to further investigate and more clearly understand the physiol. roles played by the MC5 receptor in humans and other animals.

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