title: MS-377, a selective sigma receptor ligand, indirectly blocks the action of PCP in the N-methyl-D-aspartate receptor ion-channel complex in primary cultured rat neuronal cells.
abstract: MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.
authors: Drug Discoverv Institute, Nihon Schering, Inc, Mobara-shi, Chiba, Japan. jkarasawa@schering.co.jp
authors: Jun-ichi
authors: J
authors: Karasawa
authors: Hideko
authors: H
authors: Yamamoto
authors: Toshifumi
authors: T
authors: Yamamoto
authors: Naoki
authors: N
authors: Sagi
authors: Kazutoshi
authors: K
authors: Horikomi
authors: Ichiro
authors: I
authors: Sora
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000378:metabolism; D005260:Female; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010620:Phenazocine / Q000031:analogs & derivatives*; D010622:Phencyclidine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013644:Tartrates; D014316:Tritium; D000097605:Sigma-1 Receptor
chemical_list: D014150:Antipsychotic Agents; D002118:Calcium; D016291:Dizocilpine Maleate; D007473:Ion Channels; D010620:Phenazocine; D010622:Phencyclidine; D010879:Piperazines; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D013644:Tartrates; D014316:Tritium; D000097605:Sigma-1 Receptor; C464615:1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate; C012134:SK&F 10047