Inverse agonist actions of typical and atypical antipsychotic drugs at thehuman 5-hydroxytryptamine(2C) receptor

Atypical antipsychotic drugs, which are distinguished from typical antipsyc hotic drugs by a lower incidence of extra-pyramidal side effects and less p ropensity to elevate serum prolactin levels (e.g., clozapine, olanzapine, r isperidone, quetiapine, ziprasidone), have become the most widely used trea tments for schizophrenia, although their precise mechanism of action remain s controversial. It has been suggested that this group of atypical antipsyc hotic drugs is characterized by preferentially high affinities for 5-hydrox ytryptamine (5-HT)(2A) serotonin receptors and relatively low affinities fo r D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic dr ugs (e.g., haloperidol, fluphenazine, chlorpromazine, and so on) by inverse agonist actions at the 5-HT2C-INI RNA edited isoform of the human 5-HT2C r eceptor transiently expressed in COS-7 cells. We have examined the relation ship among 5-HT2C inverse agonist potency, efficacy, and atypical antipsych otic drug status in HEK-293 cells of a large number of typical and atypical antipsychotic drugs using human embryonic kidney (HEK)-293 cells stably tr ansfected with the h5-HT2C-INI receptor. Inverse agonist actions at h5-HT2C -INI receptors were measured for both typical and atypical antipsychotic dr ugs. Thus, some typical antipsychotic drugs (chlorpromazine, mesoridazine, fluphenazine, and loxapine) were efficient inverse agonists, whereas severa l clinically effective atypical antipsychotic drugs (remoxapride, quetiapin e, sulpiride, melperone, amperozide) were not. Additionally, several drugs without significant antipsychotic actions (M100907, ketanserin, mianserin, ritanserin, and amitriptyline) were potent inverse agonists at the 5-HT2C-I NI isoform expressed in HEK-293 cells. Taken together, these results demons trate that both typical and atypical antipsychotic drugs may exhibit invers e agonist effects at the 5-HT2C-INI isoform of the human 5-HT2C receptor an d that no relationship exists between inverse agonist actions and atypicali ty.