Year: 2023
Type: article
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.
Source: Journal of Medicinal Chemistry
Authors: 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
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: National Science Foundation, American Association of Colleges of Pharmacy, High Point University, Rowan University, National Institutes of Health, University of North Carolina at Chapel Hill, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Division of Chemistry
Awards: G1232909846, G1615910521, G2476831334, MRI: Acquisition of a 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer to Support Undergraduate Research at High Point University, Low-Efficacy Dopamine D4 Receptor Partial Agonists for Cocaine Addiction, Molecular And Pharmacological Studies Of Dopamine Receptors, G6948267852, G7009490193, Dopamine D2-like Functionally Selective Agonists, Molecular And Pharmacological Studies Of Dopamine Receptors, U-Rise at Rowan University
OpenAlex ID: W4386272479