Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder.

Pharmacological targeting of the dopamine D receptor (DR)─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 DR. We identified several compounds with high DR binding affinity ( ≤ 6.9 nM) and >91-fold selectivity over other D-like receptors (DR, DR) with diverse partial agonist and antagonist profiles. Novel analogue is a potent low-efficacy DR partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC > 3). (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by DR-selective antagonists. Off-target antagonism of 5-HT or 5-HT may also contribute to these effects. Results with support further efforts to target DR in SUD treatment.