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Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

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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, Department of Biomedical & Translational Sciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States
§ Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States
*Phone: (443)740-2887. Fax: (443)740-2111. E-mail: [email protected]
Cite this: J. Med. Chem. 2016, 59, 16, 7634–7650
Publication Date (Web):August 10, 2016
https://doi.org/10.1021/acs.jmedchem.6b00860
Copyright © 2016 American Chemical Society

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    Abstract

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    The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

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