Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists.

ABSTRACT: Antagonist ligands of the melanocortin-3 and -4 receptors (MC3R, MC4R), including agouti-related protein (AGRP), are postulated to be targets for the treatment of diseases of negative energy balance. Previous studies reported the macrocyclic MC3R/MC4R antagonist c[Pro¹-Arg²-Phe³-Phe⁴-Asn⁵-Ala⁶-Phe⁷-dPro⁸], which is 250-fold less potent at the mouse (m) mMC3R and 3-fold less potent at the mMC4R than AGRP. Previous studies explored the structure-activity relationships around individual positions in this template. Herein, a multiresidue substitution strategy is utilized, combining the lead sequence with hPhe⁴, Dap⁵, Arg⁵, Ser⁶, and Nle⁷ substitutions p

SUBMITTER: Fleming KA 

PROVIDER: S-EPMC6174881 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature