期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 2, 页码 580-593出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01148
关键词
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资金
- National Institute on Drug Abuse-Intramural Research Program
- NLDA through Interagency Agreement [ADA 12003-005]
- Naval Research Laboratory
- [DA022413]
- [MH054137]
Both dopamine D-3 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.
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