Potent and selective peptide agonists of α-melanocyte stimulating hormone (αMSH) action at human melanocortin receptor 5;: their synthesis and biological evaluation in vitro

Melanocortin receptors (MC1-5R) and their endogenous ligands (melanocyte-stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor-binding affinity and agonist activity) of several cyclic analogs of alpha MSH which are potent agonists at hMC5R (EC50 below 1 nM) and of enhanced receptor subtype selectivity (more than 2000-fold versus hMC1b,3R and about 70- to 200-fold versus hMC4R). These compounds are analogs of Ac-Nle(4)-cyclo[Asp(5)-His(6)-D-Nal(2')(7)-Pip(8)-Trp(9)-Lys(10)]-NH2 (Pip: pipecolic acid) in which His(6) has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti-inflammatory actions of alpha MSH.