llosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (CaV2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497’s effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the CaV2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and CaV2.2 channel can be ruled out....

中文翻译：

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(E)-3-(呋喃-2-基)-N-(对甲苯基)丙烯酰胺在小鼠中的镇痛活性被(E)-3-(呋喃-2-基)-N-甲基-N降低-(对甲苯基)丙烯酰胺通过 α7 烟碱乙酰胆碱受体的相反调节机制

α7 烟碱乙酰胆碱受体 (nAChR) 的变构调节剂。方法：使用奥沙利铂诱导的神经性疼痛小鼠模型（2.4 mg/kg，10次注射）来测试DM497和DM490的镇痛特性。为了评估可能的作用机制，使用电生理学技术测定了这些化合物在异源表达的 α7 和 α9α10 nAChR 以及电压门控 N 型钙通道 (CaV2.2) 上的活性。结果：冷板试验表明，10 mg/kg DM497 能够减轻化疗药物奥沙利铂引起的小鼠神经性疼痛。相反，DM490既不诱导促伤害活性，也不诱导抗伤害活性，但在同等剂量（30 mg/kg）下抑制DM497的作用。这些影响不是运动协调或运动活动变化的产物。在 α7 nAChR 中，DM497 增强其活性，而 DM490 抑制其活性。此外，DM490 拮抗 α9α10 nAChR 的效力比 DM497 高 8 倍以上。相反，DM497和DM490对CaV2.2通道具有最小的抑制活性。考虑到 DM497 不会增加小鼠的探索活动，间接抗焦虑机制并不是造成观察到的抗神经病作用的原因。结论：DM497 的抗伤害活性和 DM490 的伴随抑制作用是由 α7 nAChR 上的相反调节机制介导的，而其他可能的伤害感受靶点（例如 α9α10 nAChR 和 CaV2.2 通道）的参与可以被排除...... 。