Abstract
The dissociation behaviours of aripiprazole and cariprazine at the human D(2) and D(3) receptor are evaluated. A potential correlation between kinetics and in vivo profiles, especially cariprazine's action on negative symptoms in schizophrenia, is investigated. The binding kinetics of four ligands were indirectly evaluated. After the receptor preparations were pre-incubated with the unlabelled ligands, the dissociation was initiated with an excess of [(3)H]spiperone. Slow dissociation kinetics characterizes aripiprazole and cariprazine at the D(2) receptor. At the D(3) receptor, aripiprazole exhibits a slow monophasic dissociation, while cariprazine displays a rapid biphasic behaviour. Functional ß-arrestin assays and molecular dynamics simulations at the D(3) receptor confirm a biphasic binding behaviour of cariprazine. This may influence its in vivo action, as the partial agonist could react rapidly to variations in the dopamine levels of schizophrenic patients and the ligand will not quantitatively dissociate from the receptor in one single step. With these findings novel agents may be developed that display rapid, biphasic dissociation from the D(3)R to further investigate this effect on in vivo profiles.