Kuoppamäki M, Syvälahti E, Hietala J
Department of Pharmacology, University of Turku, Finland.
Eur J Pharmacol. 1993 Apr 15;245(2):179-82. doi: 10.1016/0922-4106(93)90126-t.
The effects of the atypical antipsychotic drug, clozapine, and its two major metabolites in man, N-desmethylclozapine and clozapine N-oxide, on 5-HT1C receptor mediated phosphoinositide hydrolysis were studied in rat choroid plexus. Clozapine and N-desmethylclozapine antagonized 5-HT-stimulated phosphoinositide hydrolysis with IC50 values of 110 and 29.4 nM, respectively. Clozapine N-oxide was less potent. None of the compounds stimulated phosphoinositide hydrolysis per se. The Ki values for [3H]mesulergine displacement in choroid plexus were in accordance with phosphoinositide hydrolysis data. In conclusion, this study demonstrates that clozapine and one of its major metabolites in man, N-desmethylclozapine, are potent 5-HT1C receptor antagonists. These properties of clozapine and N-desmethylclozapine should be considered when the atypical effects of clozapine are evaluated in vivo.
在大鼠脉络丛中研究了非典型抗精神病药物氯氮平及其在人体中的两种主要代谢产物N-去甲基氯氮平和氯氮平N-氧化物对5-HT1C受体介导的磷酸肌醇水解的影响。氯氮平和N-去甲基氯氮平拮抗5-羟色胺刺激的磷酸肌醇水解，IC50值分别为110和29.4 nM。氯氮平N-氧化物的效力较低。这些化合物本身均未刺激磷酸肌醇水解。脉络丛中[3H]美舒麦角位移的Ki值与磷酸肌醇水解数据一致。总之，本研究表明氯氮平及其在人体中的一种主要代谢产物N-去甲基氯氮平是有效的5-HT1C受体拮抗剂。在体内评估氯氮平的非典型作用时，应考虑氯氮平和N-去甲基氯氮平的这些特性。
