Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor.
| Title: | Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor. |
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| Authors: | Michino M; Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Boateng CA; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University , One University Parkway, High Point, North Carolina 27268, United States.; Donthamsetti P; Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States.; Yano H; Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Bakare OM; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Bonifazi A; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Ellenberger MP; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Keck TM; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Department of Chemistry and Biochemistry, and Department of Biomedical and Translational Sciences, College of Science and Mathematics, Rowan University , 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.; Kumar V; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Zhu C; Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Verma R; Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Deschamps JR; Naval Research Laboratory , Code 6930, 4555 Overlook Avenue, Washington, DC 20375, United States.; Javitch JA; Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States.; Newman AH; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.; Shi L; Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2017 Jan 26; Vol. 60 (2), pp. 580-593. Date of Electronic Publication: 2017 Jan 05. |
| Publication Type: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Intramural; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Piperazines/*pharmacology ; Receptors, Dopamine D3/*agonists ; Receptors, Dopamine D3/*chemistry; Piperazines/chemical synthesis ; Piperazines/chemistry ; Binding Sites ; Drug Partial Agonism ; HEK293 Cells ; Humans ; Molecular Dynamics Simulation ; Protein Structure, Tertiary ; Stereoisomerism |
| 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. |
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| Grant Information: | K05 DA022413 United States DA NIDA NIH HHS; R01 MH054137 United States MH NIMH NIH HHS |
| Substance Nomenclature: | 0 (Piperazines); 0 (Receptors, Dopamine D3) |
| Entry Date(s): | Date Created: 20161217 Date Completed: 20170704 Latest Revision: 20181113 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5563258 |
| DOI: | 10.1021/acs.jmedchem.6b01148 |
| PMID: | 27983845 |
| Database: | MEDLINE |
Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Intramural; Research Support, N.I.H., Extramural