Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism.

ABSTRACT: A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D₂ receptor (D₂R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D₂R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), wh

SUBMITTER: Agren R 

PROVIDER: S-EPMC7553383 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature