Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or β-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge.

大麻素受体 1 (CB1) 是一种 G 蛋白偶联受体，是代谢紊乱的治疗靶点。已经开发了许多 CB1 拮抗剂，但它们的功能选择性和对 G 蛋白或 β-arrestin 信号传导的偏向尚未得到系统表征。在这项研究中，我们分析了带有 1-氨基哌啶（系列 I）或 4-氨基硫代吗啉 1,1-二氧化物（系列 II）部分的两个系列吡唑衍生物以及众所周知的 CB1 拮抗剂的结合亲和力和下游信号传导利莫那班和他拉那班。对系列 I 和 II 衍生物的结果分析表明，对其官能团进行了微小的结构修饰，尤其是加入了 1-氨基哌啶或 4-氨基硫代吗啉 1，1-二氧化物基序可以深刻影响它们对 G 蛋白或 β-抑制蛋白信号的偏向，并且它们的结合亲和力和功能活性可以分离。对接和分子动力学模拟表明，I 系列和 II 系列拮抗剂的结合模式主要不同在于，I 系列拮抗剂与受体形成额外的氢键，而 II 系列拮抗剂形成水桥。