Toward understanding the structural basis of partial agonism at the dopamine D3 receptor

Mayako Michino, Comfort A. Boateng, Prashant Donthamsetti, Hideaki Yano, Oluyomi M. Bakare, Alessandro Bonifazi, Michael P. Ellenberger, Thomas M. Keck, Vivek Kumar, Clare Zhu, Ravi Verma, Jeffrey R. Deschamps, Jonathan A. Javitch, Amy Hauck Newman, Lei Shi

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.

Original languageEnglish (US)
Pages (from-to)580-593
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number2
StatePublished - Jan 26 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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