Synthesis and Biological Activity of Conformationally Restricted Analogs of Milnacipran: (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, an Efficient Noncompetitive N-Methyl-d-aspartic Acid Receptor Antagonist

Abstract

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 μM, 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.