This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC₈₀ agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.

这项工作描述了 BNC210 (6-[(2,3-二氢-1 H-茚-2-基)氨基]-1-乙基-3-(4-吗啉基羰基)-1,8-萘啶-4( 1 H )-one)，α7 烟碱乙酰胆碱受体 (α7 nAChR) 的选择性小分子负变构调节剂 (NAM)。为了发现一种非镇静抗焦虑化合物，在对重点药物化学文库进行表型筛选时，使用小鼠 Light Dark (LD) 盒评估抗焦虑样活性，并使用小鼠 Open Field (OF)（暗）测试以检测镇静和/或运动效果。BNC210 表现出抗焦虑样活性，但没有可测量的镇静或运动作用。电生理学表明，BNC210 本身不会诱导 α7 nAChR 电流，但会抑制稳定表达大鼠或人 α7 nAChR 的重组 GH4C1 细胞系中EC _{80激动剂诱发的电流。}在表达 cys 环配体门控离子通道家族其他成员的细胞系上进行测试时，BNC210 没有活性。筛选了 400 多个其他靶标，未发现 BNC210 具有任何活性，这证实了其对 α7 nAChR 的选择性。在与焦虑和压力相关疾病相关的多项行为测试中，雄性小鼠和大鼠口服 BNC210 后，在高达最小有效剂量 500 倍的广泛治疗范围内，这些行为显着减少。在适当的大鼠和小鼠试验中进一步测试潜在的副作用表明，BNC210 不会产生镇静、记忆和运动障碍或身体依赖性，以及与当前抗焦虑疗法相关的症状。这些数据表明，α7 nAChR 功能的变构抑制可能代表了一种治疗焦虑和压力相关疾病的差异化方法，与目前的治疗方法相比，其安全性得到了改善。