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

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.

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

“…This is consistent with our recent finding that blockade of D 3 Rs by another set of D 3 R-selective partial agonists also inhibited intravenous heroin self-administration in wild-type mice, but not in D 3 R-knockout mice. 9 Given compound 19 ’s exceptional D 3 R-selectivity profile, the behavioral effects observed in the present study are likely mediated via blockade of central D 3 Rs. This hypothesis is supported by recent findings that genetic deletion of D 3 R in D 3 -knockout mice blocked morphine-induced hyperactivity and repeated morphine-induced locomotor sensitization.…”

“…FR1). 1,9 However, little is known as to whether D 3 R antagonists are similarly effective in attenuating the addiction-related behaviors of prescription opioids. Opioid-induced locomotor sensitization and conditioned place preference (CPP) are commonly used animal models to evaluate pharmacological agents for their utility in the treatment of addiction.…”

“…8 Nevertheless, efficacy in both animal models of other substance use disorders, including heroin, alcohol and nicotine support continued efforts toward developing D 3 R-selective antagonists and/or partial agonists that are metabolically stable and have appropriate drug-like properties for potential translation to specific drug abusing populations. 1,9,10 …”

“…9,14 Herein, we reasoned that if the 2,3-dichloro-substituted phenylpiperazine was replaced with substituents borrowed from the eticlopride structure that the new templates might serve as PPs with potentially improved D 3 R affinities, selectivities and/or metabolic stability. Hence, we incorporated another privileged D 3 R PP, the 2-methoxyphenylpiperazine, into our design to make the 3-chloro-5-ethyl-2-methoxyphenylpiperazine PP (Fig.…”

Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

“…This SAR corresponds with our previously reported 4-phenylpiperazines, wherein the 2-indole analogues are typically more D 3 R-selective than their quinoline derivatives. 45 …”