(.+-.)-(Z)-2-(Aminomethyl)-1-phenylcyclopropanecarboxamide Derivatives as a New Prototype of NMDA Receptor Antagonists

Abstract

(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

“…We found (±)-(Z)-2-aminomethyl-1-phenyl-N,N-diethylcyclopropanecarboxamide (milnacipran, 1), an efficient antidepressant due to its competitive inhibition of the reuptake of serotonin (5-HT) and noradrenaline in the CNS (18), to be a new class of non-competitive NMDA-receptor antagonists (19). As a lead for developing efficient NMDAreceptor antagonists, milnacipran has the advantage of penetrating into the brain sufficiently without serious side effects.…”

“…Design and synthesis of conformationally restricted analogs of milnacipran Although we first performed modifications of the functional groups of milnacipran (1), e.g., phenyl, diethylcarbamoyl and aminomethyl groups, the activity was not significantly improved, implying that these functional groups are important for the activity (19). Therefore, we next turned our attention to the effects of conformational changes of the molecule on the activity and designed conformationally restricted analogs of 1, in which a new method for restricting the conformation of cyclopropane derivatives was developed (20).…”

NMR-based Enantiodifferentiation of Chiral trans-2-Phenylcyclopropane Derivatives Using a Chiral Lanthanide Shift Reagent

“…Stereochemical considerations, including the optical isomerism of biomolecules, are thus of high importance in understanding biochemical and physiological mechanisms. Chiral phenylcyclopropane derivatives exhibit fungicidal, 5 pharmacological, 6 and human anti-breast cancer activities, 8 and have been used as NMDA receptor antagonists 7 and in tumor imaging with positron emission technologies. 9 Since chiral phenylcyclopropane derivatives represent various biological activities, it is useful to determine their optical purities and absolute configurations by NMR with the simple addition of CLSR.…”

Conformational Analysis of the NMDA Receptor Antagonist (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) Designed by a Novel Conformational Restriction Method Based on the Structural Feature of Cyclopropane Ring.

“…35) Although the binding affinity of (Ϯ)-1 for the NMDA receptor is not high, the compound has the advantage of sufficiently pene- trating into the brain without serious side effects, 15,16) making it a clinically useful antidepressant and therefore a good lead for an efficient NMDA receptor antagonist. This may be because the structure of milnacipran is clearly different from that of previous NMDA receptor antagonists.…”

“…We hypothesized that this structural feature of the cyclopropane ring system could be used as a conformational restriction method, and therefore designed the conformationally restricted analogs of milnacipran (Ϯ)-1. Because the primary amino function of (Ϯ)-1 is essential for the binding affinity for the NMDA receptor, 35) we assumed that the conformation of the aminomethyl moiety would significantly affect the activity of the compound. While the aminomethyl moiety is not so bulky and may freely rotate at least to some extent, the conformers A and B may be preferable to conformer C because of the serious steric repulsion with the bulky diethylcarbamoyl group in conformer C, as shown in Fig.…”