Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder
Comfort A. Boateng, Ashley N. Nilson, Rebekah Placide, Mimi L. Pham, Franziska M. Jakobs, Noelia Boldizsar, Scot McIntosh, Leia S. Stallings, Ivana V. Korankyi, Shreya Kelshikar, Nisha Shah, Diandra Panasis, Abigail Muccilli, Maria Ladik, Brianna Maslonka, Connor McBride, Moises Ximello Sanchez, Ebrar Akca, Mohammad Alkhatib, Julianna Saez, Catherine Nguyen, Emily Kurtyan, Jacquelyn DePierro, Raymond Crowthers, Dylan Brunt, Alessandro Bonifazi, Amy Hauck Newman, Rana Rais, Barbara S. Slusher, R. Benjamin Free, David R. Sibley, Kent D. Stewart, Chun Wu, Scott E. Hemby, Thomas M. Keck
Abstract
High Resolution Image Download MS PowerPoint Slide 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.