Bertron Jeanette L, Ennis Elizabeth A, Tarr Christopher J, Wright Jane, Dickerson Jonathan W, Locuson Charles W, Blobaum Anna L, Rook Jerri M, Blakely Randy D, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2016 Oct 1;26(19):4637-4640. doi: 10.1016/j.bmcl.2016.08.062. Epub 2016 Aug 21.
This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.
本信函描述了胆碱转运体（CHT）抑制剂探针ML352（VU0476201）的进一步先导优化，以及改进的体内工具VU6001221的研发。多维优化工作遇到了陡峭的构效关系（SAR），最终，对中心苯基核心电子结构的细微调整产生了VU6001221，这是一种CHT抑制剂，对胆碱摄取抑制的效力与ML352相当，但药代动力学（PK）和中枢神经系统（CNS）渗透性得到了改善。此外，VU6001221首次使在标准的临床前啮齿动物认知模型——新物体识别（NOR）中评估CHT抑制剂成为可能。我们观察到VU6001221能引起NOR的剂量反应性增加，这增加了细胞外胆碱升高对突触α7烟碱型乙酰胆碱受体产生激动作用的可能性，如果得到证实，将代表一种增强认知的新分子策略。
