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

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.