Antagonist properties of the novel antipsychotic, S16924, at cloned, human serotonin 5-HT(2C) receptors: A parallel phosphatidylinositol and calcium accumulation comparison with clozapine and haloperidol

被引：0

作者：

Cussac D. ^{[1
]}

Newman-Tancredi A. ^{[1
]}

Nicolas J.-P. ^{[2
]}

Boutin J.A. ^{[2
]}

Millan M.J. ^{[1
]}

机构：

[1] Institut de Recherches Servier, Psychopharmacology Department, F-78290 Croissy-sur-Seine, 125, Chemin de Ronde

[2] Institut de Recherches Servier, Molec. and Cell. Pharmacol. Dept., F-78290 Croissy-sur-Seine, 125, Chemin de Ronde

来源：

Naunyn-Schmiedeberg's Archives of Pharmacology | 2000年 / 361卷 / 5期

关键词：

5-HT(2C) receptors; Antipsychotic; Clozapine; Haloperidol; Phosphatidylinositol; Phospholipase C; Schizophrenia;

D O I：

10.1007/s002100000221

中图分类号：

学科分类号：

摘要：

The novel benzopyranopyrrolidine and potential antipsychotic, S16924 ((+)-2-(1-[2-(2,3-dihydrobenzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl)-1- (4-fluoro-phenyl)-ethanone), displays marked affinity for serotonin (5- HT)(1A), 5-HT(2A) and dopamine D2 receptors. Herein, we show that it also possesses high affinity for the cloned, INI isoform of h5-HT(2C) receptors (pK(i)=8.28) stably expressed in CHO cells. Similarly, clozapine (8.04) was a potent ligand, whereas haloperidol (<6.0) showed low affinity. As demonstrated by fura2-detection, S16924 concentration-dependently abolished (pK(b)=7.93) the 5-HT-induced elevation in intracellular levels of Ca2+ ([Ca2+](i)) in a CHO cell line stably expressing the INI isoform of 5- HT(2C) receptors. Further, as determined by depletion of membrane-bound levels of pre-labelled [3H]phosphatidylinositols ([3H]PI), S16924 concentration-dependently, surmountably and competitively blocked the activation of phospholipase C by 5-HT. This action was expressed with a pA2 of 7.89 according to Schild analysis. Clozapine likewise inhibited 5-HT- induced alterations in [Ca2+](i) and [3H]PI levels with PK(b)s of 7.43 and 7.84, respectively, whereas haloperidol was inactive (<5.0 in each case). Applied alone, S16924, clozapine and haloperidol modified levels of neither [Ca2+](i) nor [3H]PI. In conclusion, in analogy to clozapine, and in contrast to haloperidol, S16924 behaves as a potent and competitive antagonist at h5-HT(2C) receptors, the blockade of which may contribute to its distinctive functional profile of activity.

引用

页码：549 / 554

页数：5

共 57 条

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