Introduction. Most antipsychotics antagonize the dopamine D2 receptor (D2R) subtype as their main mechanism of action. Unfortunately, this antagonism also leads to extrapyramidal side effects. More current development of antipsychotics is focused on D2-selective partial agonists. Although several D2-selective partial agonists have been tested for the treatment of schizophrenia, only aripiprazole has made it to the market so far. It remains unclear why certain partial agonists are efficacious as a treatment for schizophrenia whereas others are not. One emerging hypothesis is that aripiprazole displays ‘stimulus bias’, that is, it promotes unique conformations of the D2R that signal selectively via certain signalling pathways and not others, and that this bias underlies its unique antipsychotic activity.
Aims. To determine if aripiprazole displays stimulus bias at the D2R and if it has a distinct pattern of bias from partial agonists with limited anti-psychotic efficacy such as S-3PPP.
Methods. The effect of various D2R ligands with known in vivo efficacy and their derivatives on both the inhibition of forskolin-induced cAMP production and the phosphorylation of ERK1/2 was determined using FlpIn CHO cells expressing the D2R. Data was analyzed using a method based upon the Black and Leff operational model of agonism to allow the quantification of stimulus bias1 .
Results. Aripiprazole is approximately 30-fold more biased towards the inhibition of cAMP production than towards ERK1/2 phosphorylation as compared to the typical D2R agonists dopamine or ropinirole and the partial agonist S-3PPP.
Discussion. Our novel analytical approaches have revealed that the antipsychotic aripiprazole displays a distinct pattern of stimulus bias as compared to the endogenous agonist dopamine or S-3PPP. This observation will provide a foundation for future studies aimed at relating in vitro activity with in vivo efficacy.