Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor.

ABSTRACT: Both dopamine D₃ receptor (D₃R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D₃R in complex with these enantiomers. Analysis of the simulation result

SUBMITTER: Michino M 

PROVIDER: S-EPMC5563258 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature