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.
The dopamine D3 receptor (D3R) is
a target for developing medications
to treat substance use disorders. D3R-selective compounds with high
affinity and varying efficacies have been discovered, providing critical
research tools for cell-based studies that have been translated to
in vivo models of drug abuse. D3R antagonists and partial agonists
have shown especially promising results in rodent models of relapse-like
behavior, including stress-, drug-, and cue-induced reinstatement
of drug seeking. However, to date, translation to human studies has
been limited. Herein, we present an overview and illustrate some of
the pitfalls and challenges of developing novel D3R-selective compounds
toward clinical utility, especially for treatment of cocaine abuse.
Future research and development of D3R-selective antagonists and partial
agonists for substance abuse remains critically important but will
also require further evaluation and development of translational animal
models to determine the best time in the addiction cycle to target
D3Rs for optimal therapeutic efficacy.
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