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Vol. 299, Issue 1, 83-89, October 2001
Departments of Biochemistry, Psychiatry and Neurosciences (B.L.R.),
the National Institute of Mental Health Psychoactive Drug Screening
Program (L.R., J.E.S., B.L.R.), Case Western Reserve University Medical
School, Cleveland, Ohio; and Departments of Psychiatry and
Pharmacology, Vanderbilt University Medical School, Nashville,
Tennessee (H.Y.M.)
Atypical antipsychotic drugs, which are distinguished from typical
antipsychotic drugs by a lower incidence of extra-pyramidal side
effects and less propensity to elevate serum prolactin levels (e.g.,
clozapine, olanzapine, risperidone, quetiapine, ziprasidone), have
become the most widely used treatments for schizophrenia, although
their precise mechanism of action remains controversial. It has been
suggested that this group of atypical antipsychotic drugs is
characterized by preferentially high affinities for 5-hydroxytryptamine (5-HT)2A serotonin receptors and relatively low affinities
for D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic drugs (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 receptor transiently
expressed in COS-7 cells. We have examined the relationship among
5-HT2C inverse agonist potency, efficacy, and atypical
antipsychotic drug status in HEK-293 cells of a large number of typical
and atypical antipsychotic drugs using human embryonic kidney (HEK)-293
cells stably transfected with the h5-HT2C-INI receptor.
Inverse agonist actions at h5-HT2C-INI receptors were
measured for both typical and atypical antipsychotic drugs. Thus, some
typical antipsychotic drugs (chlorpromazine, mesoridazine,
fluphenazine, and loxapine) were efficient inverse agonists, whereas
several clinically effective atypical antipsychotic drugs (remoxapride,
quetiapine, 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-INI isoform expressed in
HEK-293 cells. Taken together, these results demonstrate that both
typical and atypical antipsychotic drugs may exhibit inverse agonist
effects at the 5-HT2C-INI isoform of the human
5-HT2C receptor and that no relationship exists between
inverse agonist actions and atypicality.
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