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.
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.
Shuto
S
S
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Ono
S
S
Hase
Y
Y
Ueno
Y
Y
Noguchi
T
T
Yoshii
K
K
Matsuda
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D016202:N-Methylaspartate; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
D003521:Cyclopropanes; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; C015766:cyclopropanecarboxylic acid; D012701:Serotonin; D016202:N-Methylaspartate