High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice

Comfort A. Boateng, Oluyomi M. Bakare, Jia Zhan, Ashwini K. Banala, Caitlin Burzynski, Elie Pommier, Thomas M. Keck, Prashant Donthamsetti, Jonathan A. Javitch, Rana Rais, Barbara S. Slusher, Zheng Xiong Xi, Amy Hauck Newman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6195-6213
Number of pages19
JournalJournal of medicinal chemistry
Volume58
Issue number15
DOIs
StatePublished - Jul 23 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Boateng, C. A., Bakare, O. M., Zhan, J., Banala, A. K., Burzynski, C., Pommier, E., Keck, T. M., Donthamsetti, P., Javitch, J. A., Rais, R., Slusher, B. S., Xi, Z. X., & Newman, A. H. (2015). High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice. Journal of medicinal chemistry, 58(15), 6195-6213. https://doi.org/10.1021/acs.jmedchem.5b00776