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

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 (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 D₃R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D₃R knockout mice.