TY - JOUR
T1 - Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT1A receptors expressed in HeLa cells
AU - Cosi, Cristina
AU - Koek, Wouter
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2001/12/14
Y1 - 2001/12/14
N2 - Agonist and antagonist properties of antipsychotics at human (h) recombinant 5-hydroxytryptamine1A (h5-HT1A) 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-HT1A receptor (HA7 cells), appears suitable to characterize not only agonist and antagonist properties of 5-HT1A receptor ligands, but also inverse agonist properties. We therefore examined agonist, antagonist, and inverse agonist activity of antipsychotics at h5-HT1A 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-1H-dibenz[2,3:6,7,5]-oxepino- [4,5c]pyrrole (ORG 5222), were more potent h5-HT1A receptor antagonists than raclopride, olanzapine, and risperidone. Haloperidol, chlorpromazine, thioridazine, pimozide, and sertindole showed Na+-dependent inverse agonist activity at h5-HT1A 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-HT1A 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-HT1A receptors, likely by influencing receptor precoupling. Also, the manner in which compounds interact with 5-HT1A receptors appears to be related to their Kb/Ki ratio.
AB - Agonist and antagonist properties of antipsychotics at human (h) recombinant 5-hydroxytryptamine1A (h5-HT1A) 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-HT1A receptor (HA7 cells), appears suitable to characterize not only agonist and antagonist properties of 5-HT1A receptor ligands, but also inverse agonist properties. We therefore examined agonist, antagonist, and inverse agonist activity of antipsychotics at h5-HT1A 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-1H-dibenz[2,3:6,7,5]-oxepino- [4,5c]pyrrole (ORG 5222), were more potent h5-HT1A receptor antagonists than raclopride, olanzapine, and risperidone. Haloperidol, chlorpromazine, thioridazine, pimozide, and sertindole showed Na+-dependent inverse agonist activity at h5-HT1A 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-HT1A 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-HT1A receptors, likely by influencing receptor precoupling. Also, the manner in which compounds interact with 5-HT1A receptors appears to be related to their Kb/Ki ratio.
KW - 5-HT receptor
KW - Antipsychotic
KW - HA7 cell
KW - Inverse agonism
KW - [S] GTPγS binding
UR - http://www.scopus.com/inward/record.url?scp=0035861850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035861850&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(01)01493-5
DO - 10.1016/S0014-2999(01)01493-5
M3 - Article
C2 - 11755134
AN - SCOPUS:0035861850
VL - 433
SP - 55
EP - 62
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -