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...

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Published in:Journal of medicinal chemistry 2023-09, Vol.66 (17), p.12141-12162
Main Authors: Boateng, Comfort A., Nilson, Ashley N., Placide, Rebekah, Pham, Mimi L., Jakobs, Franziska M., Boldizsar, Noelia, McIntosh, Scot, Stallings, Leia S., Korankyi, Ivana V., Kelshikar, Shreya, Shah, Nisha, Panasis, Diandra, Muccilli, Abigail, Ladik, Maria, Maslonka, Brianna, McBride, Connor, Sanchez, Moises Ximello, Akca, Ebrar, Alkhatib, Mohammad, Saez, Julianna, Nguyen, Catherine, Kurtyan, Emily, DePierro, Jacquelyn, Crowthers, Raymond, Brunt, Dylan, Bonifazi, Alessandro, Newman, Amy Hauck, Rais, Rana, Slusher, Barbara S., Free, R. Benjamin, Sibley, David R., Stewart, Kent D., Wu, Chun, Hemby, Scott E., Keck, Thomas M.
Format: Article
Language:English
Subjects:
Animals
Benzothiazoles - pharmacology
Benzothiazoles - therapeutic use
Brain
Cocaine - pharmacology
Humans
Rats
Serotonin
Substance-Related Disorders
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Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c00734