Author/Authors :
Wanlong Jiang، نويسنده , , Joe A. Tran، نويسنده , , Fabio C. Tucci، نويسنده , , Beth A. Fleck، نويسنده , , Sam R. Hoare، نويسنده , , Stacy Markison، نويسنده , , Jenny Wen، نويسنده , , Caroline W. Chen، نويسنده , , Dragan Marinkovic، نويسنده , , Melissa Arellano، نويسنده , , Alan C. Foster، نويسنده , , Chen Chen، 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 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a Ki of 11 nM and an EC50 of 24 nM, while its 3R,4S-isomer 20f-2 exhibited a Ki of 8.6 and an IC50 of 65 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.
Keywords :
pyrrolidine , melanocortin-4 receptor , agonist , Antagonist , Potency , Synthesis , Efficacy
