Effects of Macrocycle Size and Rigidity on Melanocortin Receptor-1 and -5 Selectivity in Cyclic Lactam α-Melanocyte-Stimulating Hormone Analogs

The effects of the linker arm rigidity and size on melanocortin receptor selectivity were explored in a series of compounds using cyclic lactam α‐melanocyte‐stimulating hormone template. A variety of dicarboxylic acid linkers introduced between the α‐amino group of His6 and the ɛ‐amino group of Lys10 lead to high‐affinity, selective human melanocortin receptor‐1 and ‐5 (hMC1R and hMC5R) antagonists. The incorporation of hydrophilic functions into the linker arm was found to be unfavorable for both binding potency and receptor selectivity. Analogs 8 and 9 containing highly conformationally constrained hydrophobic linkers (m‐ and p‐phthalic acids) were found to be selective nanomolar range hMC1R antagonists (IC50 = 7 and 4 nm, respectively), whereas the employment of a small conformationally constrained linker (maleic acid) resulted in a high‐affinity (IC50 = 19 nm) and selective hMC5R antagonist (analog 12). These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin‐1 and ‐5 receptors.