Highly selective dopamine D3 receptor (D3R) antagonists and partial agonists based on eticlopride and the D3R crystal structure: New leads for opioid dependence treatment

Vivek Kumar, Alessandro Bonifazi, Michael P. Ellenberger, Thomas M. Keck, Elie Pommier, Rana Rais, Barbara S. Slusher, Eliot Gardner, Zhi Bing You, Zheng Xiong Xi, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7634-7650
Number of pages17
JournalJournal of Medicinal Chemistry
Volume59
Issue number16
DOIs
StatePublished - Aug 25 2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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