Abstract

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer’s disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.

摘要

碳酸酐酶激活剂 (CAA) 可以代表一种治疗阿尔茨海默病、衰老和其他需要空间学习和记忆疗法的补救措施的新方法。在一个旨在开发对某些异构体具有选择性的新型 CAA 的研究项目中，研究了三个系列的吲哚衍生物。对人 CA I、II、VA 和 VII 同种型的酶激活测定揭示了几种有效的微摩尔激活剂，对大脑相关的细胞溶质同种型 hCA VII 具有良好的选择性。分子建模研究提出了 hCA VII 和新激活剂之间复合物的理论模型，并为其调节和选择性特性提供了可能的解释。初步生物学评估表明，最有效的 CAA 之一7没有细胞毒性，能够增加人小胶质细胞中脑源性神经营养因子 (BDNF) 的释放，突出其在治疗中枢神经系统相关疾病中的可能应用。