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Vol. 302, Issue 1, 381-389, July 2002
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical
Research Institute, Wallingford, Connecticut (K.D.B., T.F.M., C.X.,
E.R., F.D.Y., P.B.M.); and CNS Research Group, Research Institute of
Pharmacological and Therapeutic Development, Otsuka Pharmaceutical Co.
Ltd., Tokushima, Japan (K.T., T.K.)
Aripiprazole is the first next-generation atypical antipsychotic with a
mechanism of action that differs from currently marketed typical and
atypical antipsychotics. Aripiprazole displays properties of an agonist
and antagonist in animal models of dopaminergic hypoactivity and
hyperactivity, respectively. This study examined the interactions of
aripiprazole with a single population of human D2 receptors to clarify
further its pharmacologic properties. In membranes prepared from
Chinese hamster ovary cells that express recombinant D2L
receptors, aripiprazole bound with high affinity to both the G
protein-coupled and uncoupled states of receptors. Aripiprazole
potently activated D2 receptor-mediated inhibition of cAMP
accumulation. Partial receptor inactivation using the alkylating agent
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)
significantly reduced the maximum effect of aripiprazole on inhibition
of cAMP accumulation. This effect was seen with concentrations of EEDQ
that did not alter the maximal inhibitory effect of dopamine.
Consistent with the expected effects of a partial agonist, increasing
concentrations of aripiprazole blocked the action of dopamine with
maximal blockade equal to the agonist effect of aripiprazole alone. The
efficacy of aripiprazole relative to that of dopamine varied from 25%
in cells that lacked spare receptors for dopamine to 90% in cells with
receptor reserve. These results, together with previous studies
demonstrating partial agonist activity at serotonin 5-hydroxytryptamine
(5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support
the identification of aripiprazole as a dopamine-serotonin system
stabilizer. The receptor activity profile may underlie the unique
activity of aripiprazole in animals and its antipsychotic activity in humans.
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