The Na_V1.8 channel is a genetically validated target for pain and it is mostly expressed in the peripheral nervous system. Based on the disclosed structures of Na_V1.8-selective inhibitors, we designed and synthesized a series of compounds by introducing bicyclic aromatic fragments based on the nicotinamide scaffold. In this research, a systematic structure−activity relationship study was carried out. While compound 2c possessed moderate inhibitory activity (IC₅₀ = 50.18 ± 0.04 nM) in HEK293 cells stably expressing human Na_V1.8 channels, it showed potent inhibitory activity in DRG neurons and isoform selectivity (>200-fold against human Na_V1.1, Na_V1.5 and Na_V1.7 channels). Moreover, the analgesic potency of compound 2c was identified in a post-surgical mouse model. These data demonstrate that compound 2c can be further evaluated as a non-addictive analgesic agent with reduced cardiac liabilities.

Na _V 1.8 通道是经过基因验证的疼痛靶标，主要在周围神经系统中表达。基于已公开的Na _V 1.8 选择性抑制剂的结构，我们通过引入基于烟酰胺支架的双环芳香片段设计并合成了一系列化合物。在本研究中，进行了系统的构效关系研究。虽然化合物2c在稳定表达人 Na _V 1.8 通道的 HEK293 细胞中具有中等抑制活性 (IC _{50 = 50.18 ± 0.04 nM)，但它在 DRG 神经元和异构体选择性中显示出强大的抑制活性（对人 Na V} 1.1、Na 的200 倍以上） _V1.5 和 Na _V 1.7 通道）。此外，在术后小鼠模型中鉴定了化合物2c的镇痛效力。这些数据表明，化合物2c可以进一步评估为一种非成瘾性镇痛剂，可降低心脏负担。