SYNTHESIS AND BIOLOGICAL-ACTIVITY OF CONFORMATIONALLY RESTRICTED ANALOGS OF MILNACIPRAN - 1-AMINOPROPYL]-N,N-DIETHYLCYCLOPROPANECARBOXAMIDE, AN EFFICIENT NONCOMPETITIVE N-METHYL-D-ASPARTIC ACID RECEPTOR ANTAGONIST

We recently demonstrated that thyl)-1-phenyl-N,N-diethylcyclopropaneca r-boxamide [milnacipran, (+/-)-1], an inhibitor of the reuptake of ser otonin (5-HT), was a noncompetitive NMDA receptor antagonist. On the b asis of the cyclopropane structure of (+/-)-1, conformationally restri cted analogs with different stereochemistries, namely 1-aminoalkyl)-N, N-diethylcyclopropanecarboxamindes (2, 3, ent-2, and ent-3), were desi gned and synthesized. Among these analogs, 2a, 2b, and 2f, with (1S,2R ,1'S)-configuration, were more efficient than milnacipran as NMDA rece ptor antagonists; these compounds significantly inhibited the binding of [H-3]MK-801 at IC50 = 0.35 +/- 0.08, 0.20 +/- 0.024, and 0.16 +/- 0 .02 mu M, respectively, and blocked the response of voltage-clamped oo cytes to NMDA, surpassing the effects of(+/-)-1. Although both the 1'- methyl analog 2a and the 1'-vinyl analog 2f, like (+/-)-1, strongly in hibited 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.