Beyond small-molecule SAR: Using the dopamine D3 receptor crystal structure to guide drug design

Abstract

The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neuropsychiatric disorders including schizophrenia, substance use and bipolar disorders. Determination of the high-resolution crystal structure of the D3R has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the D3R as a target for therapeutic intervention. We have recently discovered novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. VK4-116 was selected as a lead compound based on its in vitro profile: D3R Ki = 6.84 nM, 1700 fold D3R versus D2R binding selectivity and its metabolic stability in mouse, rat and monkey liver microsomes. VK4-116 (5-15 mg/kg, i.p.) dose-dependently blocks acquisition of oxycodone self-administration (5-15 mg/kg/infusion) and inhibits drug taking and seeking in rats trained to self-administer oxycodone. VK4-116 pretreatment (5-15 mg/kg) also blocks oxycodone-induced (1 mg/kg, i.p.) reinstatement of drug seeking in previously oxycodone trained, and subsequently behaviorally extinguished rats. Interestingly, VK4-116 (5-15 mg/kg) dose-dependently blocks naloxone-precipitated (1 mg/kg) conditioned place aversion in rats chronically treated with oxycodone (3 mg/kg, i.p.; twice daily for 7 days). Moreover, VK4-116 pretreatment shows little effect on sucrose self-administration or on the antinociceptive effects of oxycodone, tested in the hot-plate assay. Translational studies in cynomolgus monkeys are underway. Taken together, these findings suggest a crucial role for central D3R in opioid reward and dependence. Importantly, VK4-116 may serve as an effective agent for mitigating the development of prescription opioid addiction, reducing the severity of withdrawal and preventing relapse.