α‐Melanocyte‐stimulating hormone structure‐activity studies: Comparative analysis of melanotropic and CNS bioactivities

Abstract

The structure-activity relationships in vitro of alpha-MSH (alpha-melanocyte-stimulating hormone, alpha-melanotropin) analogs as determined on normal and transformed (melanoma cell) melanocyte bioassays are summarized. Specifically, the characterization of potent and metabolically stable melanotropic agonist analogs and a newly discovered antagonist of alpha-MSH are highlighted. Comparison of these data versus the known structure-activity relationships of alpha-MSH related to CNS bioactivities suggests the existence of nonclassical alpha-MSH receptor-mediated pathways or, perhaps, a yet undefined endogenous neuropeptidergic pathway(s) having different selectivities for alpha-MSH analogs. In summary, several of the alpha-MSH analogs reported here may be useful molecular probes in future strategies aimed at the identification and systematic characterization of both peripheral and central alpha-MSH receptors.

Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention

“…The small size and linear structure of a-MSH allowed for extensive structure-function studies that revealed that most of the melanotropic activity of the hormone resides in the His-Phe-Arg-Trp core sequence that is conserved in all natural melanocortins (a-, b-, c-MSH and ACTH) [19,44,96]. The best known a-MSH analog is the tridecapeptide [Nle 4 , D-Phe 7 ]-a-MSH, known as NDP-MSH, which differed from the structure of the physiological a-MSH in that the fourth amino acid residue, Methionine, was substituted by Norleucine, and the LPhenylalanine in position 7 by D-Phenylalanine [98].…”

MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA Repair

“…The physiological α-MSH is composed of 13 amino acids. Its small size and linear structure allowed for extensive structure-function studies, which revealed that most of the melanotropic activity of the hormone resides in the His 6 -Phe 7 -Arg 8 -Trp 9 core sequence [ 112 , 113 , 114 ]. The best known α-MSH analog is the tridecapeptide NDP-MSH or afamelanotide.…”

A Novel and Selective β-Melanocyte-Stimulating Hormone-Derived Peptide Agonist for Melanocortin 4 Receptor Potently Decreased Food Intake and Body Weight Gain in Diet-Induced Obese Rats

“…By removing two and four amino acid residues, respectively, from the N terminus of human ␤MSH(5-22), we obtained two nonselective, yet more potent, MC4R peptide agonists, ␤MSH(7-22) (peptide 2, Ki ϭ 4.6 nm) and ␤MSH(9 -22) (peptide 3, Ki ϭ 5.7 nm) ( Table 1). The binding affinity and functional potency of these two peptides toward MC4R and MC3R were severalfold greater than their predecessor peptide, ␤MSH (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…Early melanocortin peptide structure-activity relationships (SARs) studies focused mostly on ␣MSH and its analogs (16)(17)(18). As a result, several potent but nonselective melanocortin peptides, including (Nle 4 , D-Phe 7 ) (NDP)-␣MSH, MTII [Ac-Nle-cyclo (DHdFRWK)amide] and SHU9119 [Ac-Nle-cyclo(DHdNalRWK) amide] were developed as important tools to study MCR pharmacology.…”