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J Med Chem. 2015 Aug 13;58(15):6195-213. doi: 10.1021/acs.jmedchem.5b00776. Epub 2015 Jul 23.

High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice.

Author information

1
†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.
2
∥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.
3
§Department of Neurology, Brain Science Institute, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.

Abstract

The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.

PMID:
26203768
PMCID:
PMC4937837
DOI:
10.1021/acs.jmedchem.5b00776
[Indexed for MEDLINE]
Free PMC Article

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