Title:The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases
Volume: 17
Issue: 5
Author(s): Minying Cai and Victor J. Hruby
Affiliation:
Keywords:
Melanocortin Receptors (MCRs: MC1R, MC2R, MC3R, MC4R, MC5R); α-MSH: α -melanocyte stimulate hormone;
POMC: Proopiomelanocortin; ACTH: adrenal corticotropic hormone; GPCRs: G-protein coupled receptors; ASIP:
agouti signaling protein; AGRP: agouti related protein; MTI: Ac-Ser-Tyr-Ser-Met-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-
NH; MT-II: Ac-Nle4-c[Asp5, D-Phe7, Lys10]α-MSH(4-10)-NH2, (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). SHU9119: Ac-
Nle4-c[Asp5, D-Nal(2’)7, Lys10]α-MSH(4-10)-NH2, (Ac-Nle-c[Asp-His- D-Nal(2’)-Arg-Trp-Lys]-NH2).
Abstract: The melanocortin receptor system consists of five closely related G-protein coupled receptors
(MC1R, MC2R, MC3R, MC4R and MC5R). These receptors are involved in many of the key biological
functions for multicellular animals, including human beings. The natural agonist ligands for
these receptors are derived by processing of a primordial animal gene product, proopiomelanocortin
(POMC). The ligand for the MC2R is ACTH (Adrenal Corticotropic Hormone), a larger processed
peptide from POMC. The natural ligands for the other 4 melanocortin receptors are smaller peptides
including α-melanocyte stimulating hormone (α-MSH) and related peptides from POMC (β-MSH and
γ-MSH). They all contain the sequence His-Phe-Arg-Trp that is conserved throughout evolution. Thus, there has been
considerable difficulty in developing highly selective ligands for the MC1R, MC3R, MC4R and MC5R. In this brief review,
we discuss the various approaches that have been taken to design agonist and antagonist analogues and derivatives
of the POMC peptides that are selective for the MC1R, MC3R, MC4R and MC5R receptors, via peptide, nonpeptide and
peptidomimetic derivatives and analogues and their differential interactions with receptors that may help account for these
selectivities.
