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

详细信息    查看全文

• 作者：Mayako Michino ; Comfort A. Boateng ; Prashant Donthamsetti ; Hideaki Yano ; Oluyomi M. Bakare ; Alessandro Bonifazi ; Michael P. Ellenberger ; Thomas M. KeckVivek Kumar ; Clare Zhu ; Ravi Verma ; Jeffrey R. Deschamps ; Jonathan A. Javitch ; Amy Hauck Newman ; Lei Shi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：580-593
• 全文大小：695K
• ISSN：1520-4804

文摘

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.