Design of novel chimeric melanotropin-deltorphin analogues. Discovery of the first potent human melanocortin 1 receptor antagonist

G. Han, J. M. Quillan, K. Carlson, W. Sadée, V. J. Hruby*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


A number of novel α-melanotropin (α-MSH) analogues have been designed, synthesized, and assayed for bioactivity at the melanocortin-1 (MC1) receptor from Xenopus frog skin, and selected potent analogues were examined at recombinant human MC1, MC3, and MC4 receptors expressed in human embryonic kidney (HEK) cells. These ligands were designed from Deltorphin-II, by a new hybrid approach, which incorporates the hydrophobic tail and the address sequence of Deltorphin-II (Glu-Val-Val-Gly-NH2) and key pharmacophore elements of melanotropins. Some of the ligands designed, c[Xxx-Yyy-Zzz-Arg-Trp-Glu]-Val-Val-Gly-NH2 {XXX = nothing, Gly, β-Ala, γ-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (Cpg); ZZZ = Phe, D-Phe; D-Nal(2′)}, show high potency at melanocortin receptors. One ligand, GXH-32B-c[β-Ala-His-D-Nal(2′)-Arg-Trp-Glu]-Val-Val- Gly-NH2, the most potent of the chimeric analogues tested, displayed agonist activity at each of the MC receptor subtypes analyzed, with an EC50 of 2 nM at the amphibian MC1 receptor. In contrast, GXH-38B-c[Gly-Cpg-D-Nal-(2′)-Arg-Trp-Glu]-Val-Val-Gly-NH2 (Cpg = cyclopentyl glycine) was an antagonist with a IC50 of 43 nM at the amphibian receptor, and among the human subtypes tested, was the most potent at the MC1 receptor subtype where it also acted as an antagonist (Ki = 53 nM), which is the first potent antagonist discovered for the human MC1 receptor. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs and to design more potent ligands to treat diseases associated with the human MC1 receptor.

Original languageEnglish
Pages (from-to)810-819
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - 27 Feb 2003
Externally publishedYes

Cite this