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

Abstract

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-[ 35S]thio)-triphosphate ([ 35S] GTPγS) binding. Na +-dependent [ 35S] GTPγS 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 [ 35S] GTPγS binding with the following order of efficacy: nemonapride>ziprasidone>clozapine>ocaperidone. Tiospirone and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-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.