Novel sigma-1 pharmacological agents for photopharmacology and neuroprotection

点击翻译按钮获取中文摘要

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.