Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

[Image: see text] Pharmacological targeting of the dopamine D(4) receptor (D(4)R)—expressed in brain regions that control cognition, attention, and decision-making—could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D(4)R. We identified several compounds with high D(4)R binding affinity (K(i) ≤ 6.9 nM) and >91-fold selectivity over other D(2)-like receptors (D(2)R, D(3)R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D(4)R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC(brain/plasma) > 3). 16f (5–30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D(4)R-selective antagonists. Off-target antagonism of 5-HT(2A) or 5-HT(2B) may also contribute to these effects. Results with 16f support further efforts to target D(4)R in SUD treatment.