Novel MTII/AGRP Hybrid Analogs that Lead to Selective Ligands for the Human Melanocortin Receptors

摘要

Agouti-related protein (AGRP) is an endogenous antagonist for melanocortin receptors (MCRs). In the hypothalamus melanotropin peptide agonists act as satiety-inducing factors that mediate their action through the melanocortin-4 receptor (MC4R), whereas AGRP is an opposing orexigenic agent. AGRP has a cysteine-rich COOH-terminal domain and nuclear magnetic resonance studies (PDB: 1HYK) demonstrated that the cysteine residues in AGRP adopts a structural motif known as an inhibitor cysteine knot. This knot has been shown in vitro to be an inverse agonist with a potential in vivo to regulate the various MCRs, even in the absence of melanocortins. MTII is a super potent agonist, and it has been implicated in the treatment of sexual dysfunction and obesity, and recently, the 3D NMR structure of MTII has been reported by Ying et al. The superimposed NMR structure of the AGRP knot c[Cys~(111)-Arg-Phe-Phe-Asn-Ala-Phe-Cys~(118)] and NMR based molecular modeling derived structure of the hybrid analogs of MTII were compared. Though the primary sequence of AGRP (110-117) is totally different from that of MTII, the 3D topological structures of both pharmacophores are similar and their structures fit quite well when observed either from the alpha-carbon or from their backbone structure.