Satoshi Shuto1,*, Kiyonori Yoshii2 and Akira Matsuda1
1Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
2Department of Biochemical Engineering and Science, Kyushu Institute
of Technology, Iizuka 820-8502, Japan
*Corresponding author. FAX: +81-11-706-4980
E-mail: shu@pharm.hokudai.ac.jp
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 GluRe3/GluRz1
and GluRe4/GluRzl 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.
Keywords: Conformationally restricted analog, Cyclopropane, Milnacipran,
NMDA receptor, (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide
(PPDC)
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