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

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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.

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