834917-26-9Relevant articles and documents
A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice
Pontillo, Joseph,Tran, Joseph A.,Markison, Stacy,Joppa, Margaret,Fleck, Beth A.,Marinkovic, Dragan,Arellano, Melissa,Tucci, Fabio C.,Lanier, Marion,Nelson, Jodie,Saunders, John,Hoare, Sam R.J.,Foster, Alan C.,Chen, Chen
, p. 2541 - 2546 (2007/10/03)
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (K i > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.
4-{(2R-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl} -1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist - Design, synthesis, and characterization
Chen, Chen,Pontillo, Joseph,Fleck, Beth A.,Gao, Yinghong,Wen, Jenny,Tran, Joe A.,Tucci, Fabio C.,Marinkovic, Dragan,Foster, Alan C.,Saunders, John
, p. 6821 - 6830 (2007/10/03)
Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure-activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a Ki value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 μM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA2 value of 7.9 in the inhibition of α-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
