SAR of Melanin-concentration Hormone (MCH), an Important Regulatory Hormone in Feeding Behavior

Abstract

Melanin-concentrating hormone is a cyclic hypothalamic neuropeptide [NH₂-Asp-Phe-Asp-Met-Leu-Arg-Cys-Met-Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Gln-Val-COOH cyclo Cys-Cys (7–16)] that was first characterized in chum salmon pituitary as a hormone responsible for color changes in response to environmental stimuli [1]. In mammals, MCH appears to have evolved into an important regulatory hormone in feeding behavior [2]. The MCH peptide is expressed in the hypothalamus, a region involved in energy balance and food intake. In the hypothalamus, MCH mRNA is overexpressed and upregulated during fasting in ob/ob mice and rats. Intra-cerebroventricular injections of MCH promote feeding in mice and rats. Transgenic mice (Tg) lacking the MCH gene are lean and hypophagic, while Tg mice overexpressing MCH in the hypothalamus are hyperphagic, obese, and insulin resistant. Consequently, a potent MCH antagonist is regarded as potentially useful in therapeutic approaches to obesity management. Efforts to identify the ligands for orphan GPCRs have recently led to the discovery of the receptor for MCH [3,4]. Receptor cloning and identification of functional assays for MCHR1 receptor allow the study of receptor/ligand interaction. One possible strategy consists of chemical modifications of the natural ligand (MCH) including: N- and C-termini truncations, Ala substitutions, D-amino acid replacements, and ring size variations, with the goal to identify the critical amino acid residues responsible for agonist or antagonist activity. Here, we describe a detailed SAR of MCH peptides on MCHR1.