Novel cyclic templates of α-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors

Malcolm J. Kavarana, Der Trivedi, Minying Cai, Jinfa Ying, Matthew Hammer, Christopher Cabello, Paolo Grieco, Guoxia Han, Victor J. Hruby*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


In an effort to develop highly selective and potent agonists and/or antagonists for the hMC3 and hMC4 receptors, a new approach involving the use of linker arms and a backbone to side chain cyclization strategy was employed. Three key analogues were identified to have the required selectivity and potency at the hMC3 or hMC4 receptors, implicated to play pivotal roles in energy homeostasis and other biological effects. The novel cyclic peptide (O)C-CH2-CH2-C(O)-c-[His6-D- Phe7-Arg8-Trp9-Lys10] -NH2 (1) was found to be a highly selective and potent agonist of the hMC4 receptor. Structure-activity studies have shown that replacing the succinyl linker arm of 1 by an o-phthalic acid group and substituting a D-Nal(2′)7 residue in place of D-Phe7 results in a potent antagonist 7 at the hMC4 receptor. Furthermore, increasing the 23-membered lactam ring of 1 by one carbon atom (succinyl → glutaric acid linker) gives a highly selective and potent antagonist 9 for the hMC3 receptor. Analogues 1, 7, and 9 therefore represent the first examples of a class of cyclic melanotropin ligands with high selectivity and defined biological activities at the physiologically important hMC3 and hMC4 receptors.

Original languageEnglish
Pages (from-to)2644-2650
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number12
Publication statusPublished - 6 Jun 2002
Externally publishedYes

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