Rationale: Central dopamine D2 receptor blockade is an essential property of antipsychotic agents in the treatment of schizophrenia. However, for certain of the newer antipsychotics (e.g., sertindole), the in vitro D2 receptor binding affinity does not correlate with in vivo central dopamine antagonism.
Objective: This study aimed to investigate the effect and potency of haloperidol, pipamperone, clozapine, risperidone, sertindole, zotepine, olanzapine, and quetiapine on signaling pathways of human dopamine D2S and D3 receptors expressed in Chinese hamster ovary cells and to relate this to their dopamine antagonist potency in vivo.
Methods: Chinese hamster ovary cells, stably expressing high levels of hD2S and hD3 receptors were cultured: dopamine-stimulated [35S]-GTPgammaS binding was investigated in cell membrane preparations, and forskolin-induced cAMP formation was measured in intact cells.
Results: The antipsychotic agents inhibited dopamine-stimulated [35S]-GTPgammaS binding mediated by hD2S and hD3 receptors with potencies equal to their receptor binding affinities. The antipsychotics reversed dopamine inhibition of cAMP formation (equally well detectable with both hD2S and hD3 receptors) dose dependently at both receptors. Partial agonist effects were not observed with any of the antipsychotics. Antagonistic potencies of haloperidol, risperidone, and pipamperone in the cAMP test were equal to their receptor binding affinities. Sertindole and olanzapine were more than ten times less potent dopamine antagonists in the intact cell assay than in the assay using cell membranes; the other compounds showed less marked potency differences.
Conclusions: Olanzapine and sertindole were less efficacious dopamine antagonists in intact cell assays, possibly due to avid uptake in cells. For sertindole, the weak hD2S receptor antagonism in intact cells corresponded to a weak in vivo central dopamine antagonism assessed in rats. However, for olanzapine, hD2S receptor binding affinity correlated better with its in vivo dopamine antagonist potency. Such discrepancies may be further explained by relative differences of the compounds in penetrating into the brain.