Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
J Pharmacol Exp Ther. 2020 May;373(2):311-324. doi: 10.1124/jpet.119.263483. Epub 2020 Feb 24.
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The 7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with 7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective 7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked 7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that 7 nAChR PAMs have multiple advantages over orthosteric 7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.
治疗与中枢神经系统（CNS）疾病相关的认知缺陷，如阿尔茨海默病和精神分裂症，仍然是未满足的重大医疗需求，这给医疗保健系统带来了巨大压力。基于受体定位、强大的临床前效应、遗传学表明其与认知障碍有关，以及 7 型烟碱型乙酰胆碱受体（nAChR）正变构激动剂令人鼓舞但混杂的临床数据，7 型 nAChR 已成为治疗认知缺陷的重要靶点。重要的是，以前该受体的正变构激动剂存在非靶点活性、受体脱敏和临床前测定中的倒 U 形剂量-效应曲线，限制了其临床应用。为了克服正变构激动剂的挑战，我们已经鉴定出一种新型选择性 7 型正变构调节剂（PAM），BNC375。该化合物对相关受体具有选择性，并增强乙酰胆碱诱发的 7 型电流，对受体脱敏动力学仅有微小影响。此外，BNC375 增强大鼠海马切片中电诱发突触反应的长时程增强，并在体内增强。BNC375 的系统给药可在广泛的暴露范围内逆转东莨菪碱诱导的大鼠新物体识别和恒河猴物体检索回避（ORD）任务中的认知缺陷，没有证据表明存在倒 U 形剂量-效应曲线。该化合物还改善了老年非洲绿猴在 ORD 任务中的表现。此外，离体 C-NMR 分析表明，BNC375 治疗可增强大鼠内侧前额叶皮质中的神经递质释放。这些发现表明，7 型 nAChR PAMs 比 7 型 nAChR 正变构激动剂具有多种优势，可用于治疗与 CNS 疾病相关的认知功能障碍。
BNC375 是一种新型选择性 α7 烟碱型乙酰胆碱受体（nAChR）正变构调节剂（PAM），在体外测定中增强乙酰胆碱诱发的 α7 型电流，对脱敏动力学几乎没有影响。在体内，BNC375 在广泛的暴露范围内，在多种临床前模型中显示出强大的认知增强作用。这些结果表明，α7 nAChR PAMs 在有认知障碍的中枢神经系统疾病中具有治疗潜力。
