Pharmacology and Therapeutic Potential of Dopamine D4 Receptor Antagonists for Cocaine Use Disorder

The dopamine D4 receptor (D4R), a G protein-coupled receptor, is predominantly expressed in the prefrontal cortex in which it plays an important role in cognition, attention, and decision making. Studies have indicated D4R-selective ligands as promising therapeutic targets for the treatment of neuropsychiatric conditions such as substance use disorders (SUD). D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction. A better understanding of D4R-mediated signaling is essential to treating D4R-associated disorders, including SUD. Despite its clinical importance, there are currently no FDA approved medications that target the D4R, and for example, treat cocaine use disorder. The present study focuses on the design of D4R-selective ligands based on the parental phenylpiperazine scaffold and pharmacokinetic analysis in rat and human liver microsomes, followed by in vivo pharmacokinetic and behavioral analysis. We identified several compounds with high binding affinity and D4R selectivity (Ki ≤ 6.87 nM and >91-fold vs. other D2-like receptors (D2R, D3R)) with diverse partial agonist and antagonist profiles. Based on the affinity profiles, 5f (CAB-01-019) was selected for an in vitro metabolic stability assay in rat and human liver microsomes which displayed an acceptable stability profile. Based on these results, we moved 5f forward into in vivo pharmacokinetic analysis in rats where it displayed excellent brain penetration with AUCbrain/plasma > 3. The full antagonist 5f (5, 15 and 30 mg/kg, i.p.) was tested in cocaine self-administration studies in rats, using a within-session multidosing procedure. 5f dose-dependently decreased the number of i.v. infusions obtained for three-unit doses of cocaine under a fixed ratio (FR) FR3 schedule of reinforcement, suggesting that the selected D4R antagonist reduced the rewarding effects of cocaine. Together, these results support the development of D4R-selective antagonists for SUDs and support 5f as a new probe for studying D4R-specific behaviors.