Teresa Y. Phillips

Aryl piperazine melanocortin MC4 receptor agonists

Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC(50)=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds using in vitro cAMP functional assays in cells transfected with the MC4 or other melancortin receptors.

Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis.

The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the characterization of a small peptide mimetic MC4-R-specific agonist that possesses both high affinity (K(i)=11.3 nM) and potency (EC(50)=1.62 nM) in vitro and is capable of inhibiting feeding behavior in mice when administered intracerebroventricularly (i.c.v.). Depending on the paradigm, acute (1 h following an overnight fast) or long-term (greater than 6 h under normal nocturnal feeding conditions) feeding inhibition was observed following icv injection. No effect on long-term feeding inhibition was observed with this compound in MC4-R knockout mice, and central administration of this compound had no effect on either metabolic rate or insulin release.