1区 · 医学
Article
作者: Alkhatib, Mohammad ; Free, R Benjamin ; Sibley, David R ; Brunt, Dylan ; Crowthers, Raymond ; Newman, Amy Hauck ; Boateng, Comfort A ; Wu, Chun ; Nguyen, Catherine ; Slusher, Barbara S ; Bonifazi, Alessandro ; Ladik, Maria ; Placide, Rebekah ; McBride, Connor ; Sanchez, Moises Ximello ; Jakobs, Franziska M ; Boldizsar, Noelia ; Stewart, Kent D ; DePierro, Jacquelyn ; Korankyi, Ivana V ; Shah, Nisha ; Kurtyan, Emily ; Keck, Thomas M ; Muccilli, Abigail ; Saez, Julianna ; Panasis, Diandra ; Kelshikar, Shreya ; Rais, Rana ; Nilson, Ashley N ; Hemby, Scott E ; Pham, Mimi L ; McIntosh, Scot ; Maslonka, Brianna ; Akca, Ebrar ; Stallings, Leia S
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.