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.

中文翻译：

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发现 3-((4-Benzylpyridin-2-yl)amino)benzamides 作为有效的 GPR52 G 蛋白偏向激动剂


孤儿 GPR52 正在成为一个有前途的神经治疗靶点。采用迭代药物设计策略对先前报道的先导 4a 进行优化，从而鉴定出一系列独特的 GPR52 激动剂，例如 10a (PW0677)、15b (PW0729) 和 24f (PW0866)，其效力和功效均有所提高。有趣的是，与母体化合物 4a 相比，化合物 10a 和 24f 对 G 蛋白/cAMP 信号传导表现出更大的偏向性，并且诱导的体外脱敏显着减少，表明通过偏向激动作用降低 GPR52 β-arrestin 活性会导致 GPR52 持续激活。对化合物 15b 和 24f 的进一步探索表明其效力和功效有所提高，并且具有出色的靶标选择性，但大脑暴露有限，需要进一步优化。这些平衡且偏向的 GPR52 激动剂为研究 GPR52 激活、信号偏向以及神经精神和神经系统疾病的治疗潜力提供了重要的药理学工具。