Structure-Activity Relationships of γ-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues

Preeti Balse-Srinivasan, Paolo Grieco, Minying Cai, Dev Trivedi, Victor J. Hruby

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in α-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in γ-MSH, two different series of γ-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native γ-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH2 with Gly4) is more important for selectivity. The 2nd series is made of D-2-naphthylalanine (D-Nal(2′)) scan of the γ-MSH sequence at position 6 and 8 and the replacement of His5 with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-D-Nal(2′ )-Asp-Arg-Phe-Gly-NH2, is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-D-Nal(2′ )-Asp-Arg-Phe-Gly-NH2, is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-D-Nal(2′ )-Arg-Trp-Asp-Arg-Phe-Gly-NH2, which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.

Original languageEnglish (US)
Pages (from-to)4965-4973
Number of pages9
JournalJournal of Medicinal Chemistry
Volume46
Issue number23
DOIs
StatePublished - Nov 6 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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