748808-82-4Relevant academic research and scientific papers
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.
Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor
Pontillo, Joseph,Tran, Joseph A.,Arellano, Melissa,Fleck, Beth A.,Huntley, Rajesh,Marinkovic, Dragan,Lanier, Marion,Nelson, Jodie,Parker, Jessica,Saunders, John,Tucci, Fabio C.,Jiang, Wanlong,Chen, Caroline W.,White, Nicole S.,Foster, Alan C.,Chen, Chen
, p. 4417 - 4423 (2007/10/03)
SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.
