Semi-rigid tripeptide agonists of melanocortin receptors

A series of 30 RCO–HfR–NH2 derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC6H4CHCHCO–HfR–NH2 (13) [EC50 (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH2)3CO–HfR–NH2 (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.

Graphical abstractStructuring of the HfR–NH2 core by 4-HO-cinnamoyl led to 13 with better potency and selectivity at mMC1R than in unstructured prototype 2. Tripeptide 13 was only 11-fold less potent at mMC1R than the native tridecapeptide α-MSH (Ac-SYSMEHFRWGKPV-NH2).Figure optionsDownload full-size imageDownload as PowerPoint slide