Synthesis and biological activity of conformationally restricted analogs of milnacipran: (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxami de, an efficient noncompetitive N-methyl-D-aspartic acid receptor antagonist

Journal of Medicinal Chemistry
Satoshi ShutoAkira Matsuda

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 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.

References

May 30, 1975·The Journal of Organic Chemistry·W S MungallR L Letsinger
Jan 1, 1992·Journal of Neurochemistry·M J HoganA M Hakim
Oct 1, 1990·Trends in Pharmacological Sciences·J WillettsJ D Leander
Feb 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·J E Huettner, B P Bean
Oct 1, 1987·The Journal of General Physiology·K YoshiiH A Lester

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Citations

Mar 3, 2020·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Satoshi Shuto
Aug 30, 2013·Organic & Biomolecular Chemistry·Shuhei KawamuraSatoshi Shuto
Jun 21, 2017·Chemistry : a European Journal·Akira MizunoSatoshi Shuto
Apr 10, 2003·Chemical Reviews·Hélène LebelAndré B Charette

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