Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α 2A -adrenergic receptor (α 2A AR), seeking new α 2A AR agonists chemotypes that lack the sedation conferred by known α 2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G i and G o signaling. Experimental structures of α 2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit ‘9087 [mean effective concentration (EC 50 ) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC 50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

中文翻译：

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基于结构的非阿片类镇痛药通过 α 2A 肾上腺素受体发挥作用的发现

由于非阿片类镇痛药备受追捧，我们通过计算将超过 3.01 亿个虚拟分子与经过验证的疼痛目标 α 进行对接2A-肾上腺素能受体（α2AAR），寻找新的α2AAR 激动剂化学型缺乏已知 α 所赋予的镇静作用2AAR 药物，例如右美托咪定。我们鉴定了 17 个配体，其效力低至 12 纳摩尔，其中许多配体具有部分激动作用和优先 G我和G哦发信号。α的实验结构2AAR 与其中两种激动剂复合证实了对接预测并模板化了进一步优化。几种化合物，包括最初的对接命中'9087 [平均有效浓度（EC50）52 纳摩尔]和两个类似物，'7075 和 PS75（EC504.1 和 4.8 纳摩尔），在多个体内疼痛模型中发挥了目标镇痛活性，无需镇静。这些新发现的激动剂作为治疗先导药物很有趣，它们缺乏阿片类药物的作用和右美托咪定的镇静作用。