Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT(1A) receptors expressed in HeLa cells.
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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Division de Neurobiologie II, Centre de Recherche Pierre Fabre, 17 Ave Jean Moulin, 81106 Castres Cedex, France. cristina.cosi@pierre-fabre.com
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D014150:Antipsychotic Agents / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012964:Sodium / Q000494:pharmacology
D014150:Antipsychotic Agents; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012964:Sodium