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Effects of Macrocycle Size and Rigidity on Melanocortin Receptor‐1 and ‐5 Selectivity in Cyclic Lactam α ‐Melanocyte‐Stimulating Hormone Analogs
Author(s) -
Mayorov Alexander V.,
Han SoYeop,
Cai Minying,
Hammer Matthew R.,
Trivedi Dev,
Hruby Victor J.
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00383.x
Subject(s) - melanocortin , chemistry , linker , receptor , stereochemistry , selectivity , melanocyte stimulating hormone , melanocortin 1 receptor , cyclic peptide , antagonist , peptide , biochemistry , phenotype , computer science , catalysis , gene , operating system
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 His 6 and the ɛ ‐amino group of Lys 10 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 (IC 50 = 7 and 4 n m , respectively), whereas the employment of a small conformationally constrained linker (maleic acid) resulted in a high‐affinity (IC 50 = 19 n m ) 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.