Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the mouse melanocortin receptors. 1. Modifications at the his position

Jerry Ryan Holder, Rayna M. Bauzo, Zhimin Xiang, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


The melanocortin pathway is an important participant in obesity and energy homeostasis. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as α-melanocyte stimulation hormone (α-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp", and it has been well documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library based on the template Ac-His-DPhe-Arg-Trp-NH2, consisting of 17 members that have been modified at the His6 position (α-MSH numbering) and pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. These studies provide further experimental evidence that the His6 position can determine MC4R versus MC3R agonist selectivity and that chemically nonreactive side chains may be substituted for the imidazole ring (generally needs to be side chain protected in synthetic schemes) in the design of MC4R-selective, small-molecule, non-peptide agonists. Specifically, the tetrapeptide containing the amino-2-naphthylcarboxylic acid (Anc) amino acid at the His position resulted in a potent agonist at the mMC4R (EC50 = 21 nM), was a weak mMC3R micromolar antagonist (pA2 = 5.6, Ki = 2.5 μM), and possessed >4700-fold agonist selectivity for the MC4R versus the MC3R. Substitution of the His6 amino acid in the tetrapeptide template by the Phe, Anc, 3-(2-thienyl)alanine (2Thi), and 3-(4-pyridinyl)alanine (4-Pal) resulted in equipotency or only up to a 7-fold decrease in potency, compared to the His6-containing tetrapeptide at the mMC4R, demonstrating that these amino acid side chains may be substituted for the imidazole in the design of MC4R-selective non-peptide molecules.

Original languageEnglish (US)
Pages (from-to)2801-2810
Number of pages10
JournalJournal of medicinal chemistry
Issue number13
StatePublished - Jun 20 2002

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