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

  • J Med Chem. 2016 Aug 25;59(16):7634-50. doi: 10.1021/acs.jmedchem.6b00860.
Vivek Kumar  1 ,  Alessandro Bonifazi  1 ,  Michael P Ellenberger  1 ,  Thomas M Keck  1  2 ,  Elie Pommier  1  3 ,  Rana Rais  3 ,  Barbara S Slusher  3 ,  Eliot Gardner  1 ,  Zhi-Bing You  1 ,  Zheng-Xiong Xi  1 ,  Amy Hauck Newman  1
Affiliations
  • 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. 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.
  • 3. Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
PMID: 27508895 DOI: 10.1021/acs.jmedchem.6b00860
Abstract

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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