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Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists
Ryan E Murphy1, Pingyuan Wang1, Saghir Ali1
1Center for Addiction Sciences and Therapeutics, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
Abstract:
Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 β-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.
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