(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 have found that milnacipran, a clinically useful antidepressant due to i ts inhibition of the re-uptake of serotonin (5-HT) and noradrenaline, is al so a non-competitive NMDA-receptor antagonist. Based on the cyclopropane st ructure of milnacipran, conformationally restricted analogs were designed a nd synthesized. Of these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N, N-diethylcyclopropanecarboxamide (PPDC) is 30-fold stronger than milnacipra n as an NMDA-receptor antagonist with virtually no inhibitory effect on the neurotransmitter re-uptake. PPDC was identified as a new class of NMDA-rec eptor antagonist because it has a mode of action different from that of the previous antagonists; it selectivly binds the GluR epsilon3/GluR zeta1 and GluR epsilon4/GluR zeta1 subtype receptors in an agonist-independent allos teric manner. Functional assays of PPDC with the Xenopus oocytes system and cultured mouse neurons under voltage-clamp conditions confirmed that it ac ts as a potent NMDA-receptor antagonist. PPDC effectively protected against NMDA-induced neurotoxicity in both cultured mouse cerebral cortex and dela yed neuronal death in a gerbil ischemic model. It was also active in a rese rpine-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 u ndesirable side effects.