Highly selective dopamine D₃ receptor (D₃R) antagonists and partial agonists based on eticlopride and the D₃R crystal structure: New leads for opioid dependence treatment

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 K_i = 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.