Author/Authors :
Chen Chen، نويسنده , , Wanlong Jiang، نويسنده , , Joe A. Tran، نويسنده , , Fabio C. Tucci، نويسنده , , Beth A. Fleck، نويسنده , , Stacy Markison، نويسنده , , Jenny Wen، نويسنده , , Ajay Madan، نويسنده , , Sam R. Hoare، نويسنده , , Alan C. Foster، نويسنده , , Dragan Marinkovic، نويسنده , , Caroline W. Chen، نويسنده , , Melissa Arellano، نويسنده , , John Saunders، نويسنده ,
Abstract :
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
Keywords :
agonist , Melanocortin-4 receptor , Antagonist , Potency , stereochemistry , pyrrolidine , obesity , animal model
