title: High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice.
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.
authors.affiliation: †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.
authors.forename: Comfort A
authors.initials: CA
authors.lastname: Boateng
authors.affiliation: †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.
authors.forename: Oluyomi M
authors.initials: OM
authors.lastname: Bakare
authors.affiliation: †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.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhan
authors.affiliation: †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.
authors.forename: Ashwini K
authors.initials: AK
authors.lastname: Banala
authors.affiliation: †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.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Burzynski
authors.affiliation: †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.
authors.forename: Elie
authors.initials: E
authors.lastname: Pommier
authors.affiliation: †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.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keck
authors.affiliation: ∥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.
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.affiliation: ∥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.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: §Department of Neurology, Brain Science Institute, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: §Department of Neurology, Brain Science Institute, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: †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.
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.affiliation: †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.
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000818:Animals; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D003932:Heroin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011869:Radioligand Assay; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D012646:Self Administration
chemical_list: D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D003932:Heroin