Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

Abstract

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.

Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists

“…For instance, antagonism or partial agonism of D 2 R has been demonstrated to worsen Parkinsonism, while action at D 1 R in conjunction with levodopa administration is associated with increased LID severity. − Therefore, the pursuit of D 4 R antagonists for PD therapy demands meticulous attention to the selectivity and efficacy of the designed compounds. Recent advances in synthetic chemistry, structural biology, and pharmacology have enabled the design and characterization of diverse selective D 4 R antagonists, as exemplified in several key studies. ,− Building off of these rich structure–activity relationship data, we disclose herein the development of a novel class of potent, selective D 4 R antagonists suitable for further preclinical optimization.…”