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
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
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DOI：
10.1021/jm049278i
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发表时间：
2004-12-30
影响因子：
7.3
通讯作者：
Saunders, J
中科院分区：
文献类型：
--
作者：
Chen, C;Pontillo, J;Saunders, J
最近的研究表明，黑皮质素-4受体（MC 4 R）拮抗剂可以防止荷瘤小鼠的体重减轻，这表明临床上用于治疗恶病质。在我们的努力，以开发有效的和选择性的拮抗剂的人MC 4 R，我们设计的哌嗪苄胺轴承2，4-二氯苯丙氨酸，通过利用信息来自结构-活性关系的MC 4 R激动剂和突变的MC 4 R和肽配体的结果。在已知的MC 4 R激动剂如6的基础上，我们成功地合成了有效的MC 4 R拮抗剂10，其结合亲和力的Ki值为1.8 nM。10在10 μ M浓度下不刺激表达人MC 4受体的HEK 293细胞中的cAMP释放。Schild分析表明10是一种竞争性的功能性拮抗剂，其抑制α-MSH刺激的cAMP积累的pA（2）值为7.9。10在大鼠中静脉内给药时也渗透到脑中。
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 K-i 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 muM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.