Inverse agonist properties of antipsychotic agents at cloned, human (h) serotonin (5-HT)(1B) and h5-HT(1D) receptors.
The actions of diverse antipsychotics at cloned h5-HT(1B) and h5-HT(1D) receptors were examined employing [3H]-GR125,743 and [35S]-GTPgammaS for determination of affinities and efficacies, respectively. Compared with hD(2) receptors, haloperidol, chlorpromazine and olanzapine showed markedly (>100-fold) lower affinity for h5-HT(1D) and h5-HT(1B) receptors at which they expressed inverse agonist properties. Clozapine, risperidone and ocaperidone likewise behaved as inverse agonists at h5-HT(1B) and h5-HT(1D) receptors but their affinities were only approximately 10-fold lower than at hD(2) receptors. Moreover, ziprasidone, S16924 and ORG5222 interacted at h5-HT(1B) and h5-HT(1D) receptors with affinities similar to hD(2) sites. While S16924 and ORG5222 were inverse agonists at h5-HT(1B) and h5-HT(1D) sites, ziprasidone was an inverse agonist at h5-HT(1D) receptors yet a partial agonist at h5-HT(1B) receptors. These actions of antipsychotics were abolished by the selective, neutral antagonist, S18127. In conclusion, with the exception of ziprasidone, all antipsychotics were inverse agonists at h5-HT(1B) and h5-HT(1D) receptors, although they differed markedly in their potency at these sites as compared to hD(2) receptors.
Audinot
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V
Dept. of Molecular and Cellular Pharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, Paris, France.
Newman-Tancredi
A
A
Cussac
D
D
Millan
M J
MJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D014150:Antipsychotic Agents; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate)