Effects of (-)-stepholidine on NMDA receptors: comparison with haloperidol and clozapine.
OBJECTIVE
To examine whether (-)-stepholidine (SPD) has a direct effect on the N-methyl- D-aspartic acid receptors (NMDAR) containing the NMDA receptor subunits NR2A or NR2B and to compare its effect with those of haloperidol (Hal) and clozapine (Cloz).


METHODS
NMDAR was transiently expressed in human embryonic kidney 293 (HEK293) cells. Changes in intracellular calcium concentration ([Ca2+]i) induced by NMDAR activation were monitored with Fura-2 ratio imaging techniques.


RESULTS
SPD had no significant effects on either subunit of NMDAR at a concentration of less than 100 micromol/L. Hal selectively inhibited NMDAR containing the NR2B subunit, whereas Cloz inhibited both subunits of NMDAR. Although both Hal and Cloz inhibited NR1a/NR2B receptor-mediated Ca2+ influx, their effects were different. Hal was more potent and had a faster peak effect than Cloz.


CONCLUSIONS
Both Hal and Cloz inhibit NMDAR-mediated function, whereas SPD produced only a little inhibition at a high concentration. Based on our other studies, the modulation of SPD on NMDAR function may be via D1 receptor action underlying an indirect mechanism.
Gu
Wei-hua
WH
Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Yang
Shen
S
Shi
Wei-xing
WX
Zhen
Xue-chu
XC
Jin
Guo-zhang
GZ
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001599:Berberine / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003024:Clozapine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000378:metabolism*; D006801:Humans; D021122:Protein Subunits / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D014150:Antipsychotic Agents; D021122:Protein Subunits; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D001599:Berberine; C010513:stepholidine; D003024:Clozapine; D006220:Haloperidol; D002118:Calcium