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Selected Works of Thomas M. Keck
Article
Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor
Journal of Medicinal Chemistry (2017)
  • Mayako Michino, Cornell University
  • Comfort A. Boateng, National Institute on Drug Abuse
  • Prashant Donthamsetti, Columbia University
  • Hideaki Yano, Columbia University
  • Oluyomi M. Bakare, National Institutes of Health
  • Alessandro Bonifazi, National Institute on Drug Abuse
  • Michael P. Ellenberger, National Institutes of Health
  • Thomas M. Keck, Rowan University
  • Vivek Kumar, National Institutes of Health
  • Clare Zhu
  • Ravi Verma, National Institute on Drug Abuse
  • Jeffrey R. Deschamps, United States Naval Research Laboratory
  • Jonathan A. Javitch, Columbia University
  • Amy Hauck Newman, National Institute on Drug Abuse
  • Lei Shi, Cornell University
Link
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 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.
Disciplines
Publication Date
January 26, 2017
DOI
10.1021/acs.jmedchem.6b01148
Citation Information
Mayako Michino, Comfort A. Boateng, Prashant Donthamsetti, Hideaki Yano, et al.. "Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor" Journal of Medicinal Chemistry Vol. 60 Iss. 2 (2017) p. 580 - 593 ISSN: 1520-4804
Available at: http://works.bepress.com/thomas-keck/10/