Discovery of 3‑((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists

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.

孤儿GPR52正逐渐成为极具潜力的神经治疗靶点。本研究采用迭代药物设计策略，对此前报道的先导化合物4a进行结构优化，最终筛选得到一系列活性与效能均得到提升的新型GPR52激动剂，包括10a（PW0677）、15b（PW0729）以及24f（PW0866）。值得注意的是，与母本化合物4a相比，化合物10a与24f对G蛋白/环磷酸腺苷（cAMP）信号通路展现出更强的偏向性，且诱导的体外脱敏反应显著更弱，这表明通过偏向性激动降低GPR52的β-抑制蛋白（β-arrestin）活性，可实现GPR52的持续激活。对化合物15b与24f的进一步研究显示，二者的活性与效能均得到改善，且具备优异的靶点选择性，但脑内暴露量有限，仍需开展后续优化工作。上述兼具平衡特性与偏向性的GPR52激动剂，为研究GPR52激活、信号通路偏向性以及其在神经精神与神经系统疾病中的治疗潜力提供了重要的药理学工具。