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Eur J Pharmacol. 2001 Dec 14;433(1):55-62.

Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT(1A) receptors expressed in HeLa cells.

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Division de Neurobiologie II, Centre de Recherche Pierre Fabre, 17 Ave Jean Moulin, 81106 Castres Cedex, France.


Agonist and antagonist properties of antipsychotics at human (h) recombinant 5-hydroxytryptamine (h5-HT(1A)) receptor have been examined previously in transfected Chinese hamster ovary (CHO) cells using 5'-O-(3-[(35)S]thio)-triphosphate ([(35)S] GTP gamma S) binding. Na(+)-dependent [35S] GTP gamma S binding to membranes from human epithelioid carcinoma (HeLa) cells, expressing 500 fmol/mg protein of h5-HT(1A) receptor (HA7 cells), appears suitable to characterize not only agonist and antagonist properties of 5-HT(1A) receptor ligands, but also inverse agonist properties. We therefore examined agonist, antagonist, and inverse agonist activity of antipsychotics at h5-HT(1A) receptor in HA7 cells. Some antipsychotics had agonist activity and stimulated [(35)S] GTP gamma S binding with the following order of efficacy: nemonapride>ziprasidone>clozapine>ocaperidone. Tiospirone and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7,5]-oxepino-[4,5c]pyrrole (ORG 5222), were more potent h5-HT(1A) receptor antagonists than raclopride, olanzapine, and risperidone. Haloperidol, chlorpromazine, thioridazine, pimozide, and sertindole showed Na(+)-dependent inverse agonist activity at h5-HT(1A) receptor that could be antagonized by (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide [(s)-WAY 100135]. These results are further evidence that interactions with h5-HT(1A) receptors could play a role in the pharmacological profile of certain antipsychotics, and that Na(+) affects the ability to detect inverse agonist activity at h5-HT(1A) receptors, likely by influencing receptor precoupling. Also, the manner in which compounds interact with 5-HT(1A) receptors appears to be related to their K(b)/K(i) ratio.

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