Differences in agonist/antagonist properties at human dopamine D(2) receptors between aripiprazole, bifeprunox and...

Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms.