There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

中文翻译：

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新型取代氨基甲酰基/酰胺基/杂芳基二烷基哌嗪盐对 α9* nAChR 的激动剂选择性及其对疼痛和炎症的治疗意义的探索

迫切需要非阿片类药物治疗慢性和神经性疼痛，以在不断升级的阿片类药物危机中提供有效的替代方案。这项研究引入了针对 α9 烟碱乙酰胆碱受体 (nAChR) 亚基的新型化合物，该亚基对于疼痛调节、炎症和内耳功能至关重要。具体来说，它确定了新型取代的氨基甲酰基/酰胺基/杂芳基二烷基哌嗪鎓碘化物作为对人α9和α9α10的选择性优于α7 nAChR的有效激动剂，特别是化合物3f、3h和3j。化合物3h (GAT2711) 作为 α9 nAChR 的完全激动剂具有 230 nM 的效力，其选择性是 α7 的 340 倍。化合物3c对 α9α10 的选择性是对 α9 nAChR 的 10 倍。化合物2、3f和3h抑制 THP-1 细胞中 ATP 诱导的白细胞介素 1β 释放。 α7 基因敲除小鼠完全保留了3 小时的镇痛活性，表明镇痛作用可能是通过 α9* nAChR 介导的。我们的研究结果为开发 α9* 特异性疼痛疗法提供了蓝图。