Shuto S, Ono S, Hase Y, Ueno Y, Noguchi T, Yoshii K, Matsuda A
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
J Med Chem. 1996 Nov 22;39(24):4844-52. doi: 10.1021/jm960495w.
We recently demonstrated that (+/-)-(Z)-2-(aminomethyl)-1-phenyl-N,N-diethylcyclopropanecarboxamide [milnacipran, (+/-)-1], an inhibitor of the reuptake of serotonin (5-HT), was a noncompetitive NMDA receptor antagonist. On the basis of the cyclopropane structure of (+/-)-1, conformationally restricted analogs with different stereochemistries, namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamindes (2, 3, ent-2, and ent-3), were designed and synthesized. Among these analogs, 2a, 2b, and 2f, with (1S,2R,1'S)-configuration, were more efficient than milnacipran as NMDA receptor antagonists; these compounds significantly inhibited the binding of [3H]MK-801 at IC50 = 0.35 +/- 0.08, 0.20 +/- 0.024, and 0.16 +/- 0.02 microM, respectively, and blocked the response of voltage-clamped oocytes to NMDA, surpassing the effects of (+/-)-1. Although both the 1'-methyl analog 2a and the 1'-vinyl analog 2f, like (+/-)-1, strongly inhibited 5-HT uptake in vitro, the corresponding 1'-ethyl analog 2b was devoid of the inhibitory effect on 5-HT uptake, while it was about 30 times more potent as an NMDA receptor antagonist than (+/-)-1.
我们最近证明,(±)-(Z)-2-(氨甲基)-1-苯基-N,N-二乙基环丙烷甲酰胺[米那普明,(±)-1],一种血清素(5-HT)再摄取抑制剂,是一种非竞争性NMDA受体拮抗剂。基于(±)-1的环丙烷结构,设计并合成了具有不同立体化学的构象受限类似物,即1-苯基-2-(1-氨基烷基)-N,N-二乙基环丙烷甲酰胺(2、3、对映体-2和对映体-3)。在这些类似物中,具有(1S,2R,1'S)构型的2a、2b和2f作为NMDA受体拮抗剂比米那普明更有效;这些化合物分别在IC50 = 0.35±0.08、0.20±0.024和0.16±0.02 microM时显著抑制[3H]MK-801的结合,并阻断电压钳制卵母细胞对NMDA的反应,超过了(±)-1的作用。尽管1'-甲基类似物2a和1'-乙烯基类似物2f与(±)-1一样,在体外强烈抑制5-HT摄取,但相应的1'-乙基类似物2b对5-HT摄取没有抑制作用,而其作为NMDA受体拮抗剂的效力比(±)-1高约30倍。