Shuto S, Takada H, Mochizuki D, Tsujita R, Hase Y, Ono S, Shibuya N, Matsuda A
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
J Med Chem. 1995 Jul 21;38(15):2964-8. doi: 10.1021/jm00015a019.
(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.
(±)-(Z)-2-(氨甲基)-1-苯基环丙烷-N,N-二乙基甲酰胺（米那普明，1）是一种临床常用的抗抑郁药，其衍生物通过改进方法制备，并作为N-甲基-D-天冬氨酸（NMDA）受体拮抗剂进行评估。其中，米那普明（1）、其N-甲基和N,N-二甲基衍生物（分别为7和8）以及在氨甲基部分的同系物12在体外对该受体具有结合亲和力（半数抑制浓度：1，6.3±0.3微摩尔/升；7，13±2.1微摩尔/升；8，88±1.4微摩尔/升；12，10±1.2微摩尔/升）。这些化合物还能保护小鼠免受NMDA诱导的致死作用。由于其独特结构，这些化合物有望成为设计高效NMDA受体拮抗剂的新型原型，这种结构使其明显区别于已知的该受体竞争性和非竞争性拮抗剂。
