一种新型高效非竞争性AMPA受体拮抗剂的发现。

Discovery of a novel and highly potent noncompetitive AMPA receptor antagonist.

作者信息

Gitto Rosaria, Barreca Maria Letizia, De Luca Laura, De Sarro Giovambattista, Ferreri Guido, Quartarone Silvana, Russo Emilio, Constanti Andrew, Chimirri Alba

机构信息

Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy.

出版信息

J Med Chem. 2003 Jan 2;46(1):197-200. doi: 10.1021/jm0210008.

DOI:10.1021/jm0210008

PMID:12502375

Abstract

N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.

摘要

基于分子模拟研究，设计并合成了N-乙酰基-1-芳基-6,7-二甲氧基-1,2,3,4-四氢异喹啉衍生物，作为潜在的非竞争性AMPA受体拮抗剂。声音诱发惊厥试验表明，这类化合物具有抗惊厥特性。特别是，10c比他拉莫林（2）更有效，他拉莫林是一种非竞争性AMPA受体拮抗剂，目前正在进行III期试验作为抗癫痫药物。此外，电生理研究表明，10c是一种高效的AMPA受体非竞争性调节剂。