Abstract
The dissociation behaviours of aripiprazole and cariprazine at the human D2 and D3 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 [3H]spiperone. Slow dissociation kinetics characterizes aripiprazole and cariprazine at the D2 receptor. At the D3 receptor, aripiprazole exhibits a slow monophasic dissociation, while cariprazine displays a rapid biphasic behaviour. Functional ß-arrestin assays and molecular dynamics simulations at the D3 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 D3R to further investigate this effect on in vivo profiles.
Highlights
Schizophrenia is a group of neurological diseases characterized by specific symptom complexes
Our findings suggest that cariprazine’s biphasic properties are connected to a metastable binding pose
Given the high affinity and the fast koff from the D3 receptor, the kobs should be fast, which could result in rebinding effects in the assay
Summary
Cariprazine and aripiprazole display similar dissociation behaviours at the D2R, but differ at the D3R. Given the high affinity and the fast koff from the D3 receptor, the kobs should be fast, which could result in rebinding effects in the assay To check this possibility, different concentrations of cariprazine (0.2 and 40 times Ki value, n = 1) were evaluated, the biphasic nature of its dissociation remained. The translation of an in vitro/in silico biphasic behaviour to in vivo effects remains to be elucidated and requires more research on the origin of negative symptoms. By elucidating the binding profile of cariprazine the insights on receptor interaction at the D3R were broadened and future evaluation of novel antipsychotic drugs with special focus on the negative symptoms has gained an interesting aspect. A step in the understanding and improvement of antipsychotic therapy was made and future approaches may benefit from specialized agents for this diverse symptom complex
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
