(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

Abstract

We have found that milnacipran, a clinically useful antidepressant due to its inhibition of the re-uptake of serotonin (5-HT) and noradrenaline, is also a non-competitive NMDA-receptor antagonist. Based on the cyclopropane structure of milnacipran, conformationally restricted analogs were designed and synthesized. Of these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) is 30-fold stronger than milnacipran as an NMDA-receptor antagonist with virtually no inhibitory effect on the neurotransmitter re-uptake. PPDC was identified as a new class of NMDA-receptor antagonist because it has a mode of action different from that of the previous antagonists; it selectivly binds the GluRε3/GluRζ1 and GluRε4/GluRζl subtype receptors in an agonist-independent allosteric manner. Functional assays of PPDC with the Xenopus oocytes system and cultured mouse neurons under voltage-clamp conditions confirmed that it acts as a potent NMDA-receptor antagonist. PPDC effectively protected against NMDA-induced neurotoxicity in both cultured mouse cerebral cortex and delayed neuronal death in a gerbil ischemic model. It was also active in a reserpine-treated mouse Parkinsons disease model. Thus, PPDC may be a candidate for a clinically useful NMDA-receptor antagonist, since the development of previous NMDA-receptor antagonists as drugs has been hindered by various undesirable side effects.