Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias

While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal βarrestin-mediated signaling because MOR agonist-treated βarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/βarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.

尽管μ阿片受体（mu opioid receptor, MOR）激动剂作为广谱镇痛药效果尤为显著，但要将其镇痛作用与诸多不良副作用明确区分开来，却始终极具挑战。近年来，诸多研究团队致力于开发仅能诱导极少量β阻遏蛋白（βarrestin）介导信号通路的MOR激动剂——此前研究发现，经MOR激动剂处理的β阻遏蛋白2（βarrestin2）基因敲除小鼠，其抗伤害感受作用显著增强，同时呼吸抑制与快速耐受性均大幅减轻。目前已有大量数据支持这一前提：G蛋白信号通路（G protein signaling）偏向性MOR激动剂可作为有效的镇痛药物。我们此前的研究表明，在同一化学系列中，偏向性程度与呼吸安全指数（respiratory safety index）呈线性相关。本文中，我们将介绍哌啶苯并咪唑酮（piperidine benzimidazolone）类MOR激动剂的合成与优化工作，这类化合物展现出跨度广泛的偏向性（G/βarr2）。我们明确了影响化合物活性与最大化偏向性的结构特征，并证实诸多化合物具备优异的成药性质，例如较长的半衰期（half-lives）与出色的血脑屏障穿透能力（brain penetration）。