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

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.