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 ε-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.