Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

Pharmacological targeting of the dopamine D4 receptor
(D4R)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 D4R. We identified
several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity
over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist,
metabolically stable in rat and human liver microsomes, and has excellent
brain penetration in rats (AUCbrain/plasma > 3). 16f (5–30 mg/kg, i.p.) dose-dependently decreased iv
cocaine self-administration in rats, consistent with previous results
produced by D4R-selective antagonists. Off-target antagonism
of 5-HT2A or 5-HT2B may also contribute to these
effects. Results with 16f support further efforts to
target D4R in SUD treatment.