(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (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 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 GluRepsilon3/GluRzeta1 and GluRepsilon4/GluRzeta1 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.
Shuto
S
S
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. shu@pharm.hokudai.ac.jp
Yoshii
K
K
Matsuda
A
A
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000078764:Milnacipran; D008968:Molecular Conformation; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D003521:Cyclopropanes; D018691:Excitatory Amino Acid Antagonists; D000078764:Milnacipran; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; C114194:1-phenyl-2-(1-amino-2-propynyl)-N,N-diethylcyclopropanecarboxamide