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      High Affinity Dopamine D 3 Receptor (D 3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D 3R Knockout Mice

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          Abstract

          The dopamine D 3 receptor (D 3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D 3R-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 D 3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D 3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D 3R has been observed. Several high affinity D 3R antagonists, including compounds 16 ( K i = 0.12 nM) and 32 ( K i = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 ( 6). Notably, 16 and the classic D 3R antagonist SB277011A ( 2) were effective in reducing self-administration of heroin in wild-type but not D 3R knockout mice.

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          Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.

          Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.
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            Opiate versus psychostimulant addiction: the differences do matter.

            The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction - hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction - all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research.
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              PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys.

              Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.
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                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                23 July 2015
                13 August 2015
                23 July 2016
                : 58
                : 15
                : 6195-6213
                Affiliations
                []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 & Biochemistry, College of Science and Mathematics, Department of Biomedical & Translational Sciences, School of Biomedical Science & Health Professions, Rowan University , 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States
                [§ ]Department of Neurology, Brain Science Institute, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States
                []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
                Author notes
                [* ]Phone: (443)-740-2887. Fax: (443)-740-2111. E-mail: anewman@ 123456intra.nida.nih.gov .
                Article
                10.1021/acs.jmedchem.5b00776
                4937837
                26203768
                1e491033-9e7f-4eed-8ffb-357431fe8c85
                Copyright © 2015 American Chemical Society

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                : 21 May 2015
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                jm5b00776
                jm-2015-00776f

                Pharmaceutical chemistry
                Pharmaceutical chemistry

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