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

Abstract

alphaMSH has generally been accepted as the endogenous ligand for melanocortin 4 receptor (MC4R), which plays a major role in energy homeostasis. Targeting MC4R to develop antiobesity agents, many investigators have performed a structure-activity relationship (SAR) studies based on alphaMSH structure. In this report, we performed a SAR study using human betaMSH (5 - 22) (DEGPYRMEHFRWGSPPKD, peptide 1) as a lead sequence to develop potent and selective agonists for MC4R and MC3R. The SAR study was begun with a truncation of N terminus of betaMSH (5 - 22) together with acetylation of the N terminus and amidation of the C terminus of the peptide. Introduction of a cyclic disulfide constrain and replacement of L-Phe with D-Phe afforded a super potent agonist (peptide 5). Furthermore truncation at the C terminus generated a small and potent MC4R and MC3R agonist (Ac-YRcyclo[CEHdFRWC]amide, peptide 6), which exhibited no MC5R and greatly reduced MC1R activity. Molecular modeling of Ac-YRcyclo[CEHdFRWC]amide (peptide 6) revealed that Arg2 in the peptide formed a salt bridge with Glu4. Subcutaneous or intracerebroventricular administration of peptide 6 in rats showed potent in vivo efficacy as evidenced by its effects in reducing energy balance, increasing fat use, and decreasing weight gain in both acute and chronic rat metabolic studies. Furthermore, the antiobesity effect by peptide 6 was manifested only in wild-type but not MC4R-deficient mice, indicating that antiobesity effects of the peptide were attributed largely through MC4R but not MC3R agonist activity of the peptide.

Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity

“…In turn, this knowledge has clarified the relevance of the leptin-melanocortin pathway as a target for pharmacologic intervention in patients with severe obesity. Peptide agonists of the leptin receptor, 64 β-MSH-derived agonists, 65 and small molecule and peptide MC4R agonists 66 are all potential therapies under development. The regulation of food intake and body weight is complex.…”

The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo

“…These inputs to MC4R neurons respond to a cascade of homeostatic cues either from the circulation or through vagal signals in order to regulate MC4R activity (Cone, 2005). Activation of the MC4R by α-MSH, or its synthetic analogues, generally leads to weight loss (Hsiung et al, 2005), due to a reduction in caloric intake and an increase in energy expenditure. Conversely, blockade of MC4R by AgRP results in robust increases in feeding as well as decreases in energy expenditure (Graham et al, 1997; Ollmann et al, 1997).…”

Pharmacotherapy for obesity

“…MC4R agonists have been shown to decrease food intake and body weight in rodents [48]. Although most human obesity is polygenic in origin, MC4R mutations are thought to be the most common cause of monogenic obesity in humans.…”