Novel sigma-1 pharmacological agents for photopharmacology and neuroprotection

神经退行性疾病（ND），特别是阿尔茨海默病（AD）、肌萎缩侧索硬化（ALS）和亨廷顿病（HD），构成了人类健康的主要问题。在最有前途的治疗轨道中，一些学术团队和制药公司正在探索靶向细胞内伴侣-sigma-1受体（S1 R）的药物。然而，即使一些候选药物（blarcamesine，pridopidine）可能很快并有望成为第一批获得批准的S1 R药物，在AD和HD的II期临床试验中取得成功，仍需要找到最佳的化合物和创新的治疗策略，以更好地实施有效的基于S1 R的治疗。此外，创新的药理学工具也是至关重要的，以更好地了解S1 R的作用机制（MoA）。这是本项目的定位，这将得益于药物化学家之间正在进行的合作-教授。M.德克尔在维尔茨堡的实验室，神经药理学家T.莫里斯在蒙彼利埃的研究小组和细胞生物学家--T. P.苏博士在巴尔的摩的实验室。该项目结合了创新的化学和药理学研究，旨在开发创新的生物药理学工具。（分子探针），以能够解决关于ND中S1 R的神经保护作用的未决问题，并探索基于伴随的S1 R活化和丁酰胆碱酯酶（BChE）抑制实现AD中有效神经保护的新假设，BChE也是我们实验室目前正在探索的神经保护的新靶点。我们的具体目标是：（1）设计和验证基于S1 R激动剂和拮抗剂的新型生物药理学探针，以高时空控制S1 R活性，并进一步研究S1 R抑制或激活的急性和慢性效应;（2）研究S1 R激动剂和BChE抑制剂之间的药物组合的潜力，并开发具有过度相加的神经保护特性的新型杂合S1 R-BChE化合物，基于彻底的结构-活性关系（SAR）、生物活性的测定和杂合分子的协同活性的分子MoA的检查以及与S1 R激动剂、BChE抑制剂（BChEI）及其组合的比较。

Neurodegenerative diseases (NDs), and particularly Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), constitute a major issue for human health. Among the most promising therapeutic tracks, several academic teams and pharma companies are now exploring drugs targeting an intracellular chaperone, the sigma-1 receptor (S1R). However, even if some drug candidates (blarcamesine, pridopidine) may soon and hopefully be the first-in-class S1R drugs approved, with successful results in phase II clinical trials for AD and HD, best-in-class compounds and innovative therapeutic strategies are still to be found to better implement effective S1R-based therapies. Moreover, innovative pharmacological tools are also crucially needed to better understand the S1R mechanism of action (MoA). This is the positioning of the present project, which will take benefit from ongoing collaborations between medicinal chemists –Prof. M. Decker's lab in Würzburg–, neuropharmacologists –Dr T. Maurice's team in Montpellier–, and cellular biologists –Dr T.P. Su's lab in Baltimore. The project combines innovative chemistry and pharmacological studies and aims to develop innovative photopharmacological tools (molecular probes) to enable addressing open questions regarding the neuroprotective effects of S1R in NDs and explore a novel hypothesis to achieve efficient neuroprotection in AD based on concomitant S1R activation and butyrylcholinesterase (BChE) inhibition, with BChE being a novel target also in neuroprotection that our labs are currently exploring. Our specific aims are: (1) to design and validate novel photopharmacological probes, based on S1R agonists and antagonists, to control with high spatio-temporal control S1R activity and further investigate acute and chronic effects of S1R inhibition or activation; (2) to examine the potential of drug combination between a S1R agonist and a BChE inhibitor and to develop novel hybrid S1R-BChE compounds with over-additive neuroprotective properties, based on thorough structure-activity relationships (SARs), determination of biological activities, and examination of the molecular MoA of synergic activities of hybrid molecules and comparison with of S1R agonists, BChE inhibitors (BChEIs) and combinations thereof.