Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

The dopamine D4 receptor (D4R), a G protein-coupled receptor, is predominantly expressed in brain regions that control cognition, attention, and decision making. Previous studies have indicated that D4R-targeted ligands could be promising therapeutic targets for the treatment of several neuropsychiatric conditions, including substance use disorders (SUDs). There are currently no FDA-approved medications that selectively target D4Rs. New ligands may facilitate better understanding of the role of D4R-mediated signaling in drug-taking and drug-seeking behaviors. The present study focuses on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.87 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Based on receptor affinity and functional analyses, 5f was identified as a potent low-efficacy partial agonist of the D4R and selected for further investigation. 5f was metabolically stable in rat and human liver microsome assays and displayed excellent brain penetration in rats. Using a within-session multidosing procedure, 5f (5, 15 and 30 mg/kg, i.p.) dose-dependently decreased i.v. infusions of three-unit doses of cocaine under a fixed-ratio (FR) FR3 schedule of reinforcement. These results are consistent with previous results produced by D4R-selective antagonists in SUD models, however off-target antagonism of 5-HT2A or 5-HT2B receptors may also contribute to these effects. Results with compound 5f support further efforts to target D4R in the treatment of SUDs. Further development of the benzothiazole scaffold may engineer out any serotonergic activity.