Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration

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• 作者：Francisco J. Mart铆nez-Sanz ; Roc铆o Lajar铆n-Cuesta ; Ana J. Moreno-Ortega ; Laura Gonz谩lez-Lafuente ; Jose C. Fern谩ndez-Morales ; Raquel L贸pez-Arribas ; Mar铆a F. Cano-Abad ; Crist贸bal de los R铆os
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：September 16, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：1626-1636
• 全文大小：517K
• ISSN：1948-7193

文摘

Mitochondria regulate cellular Ca²⁺ oscillations, taking up Ca²⁺ through its uniporter and releasing it through the mitochondrial sodium/calcium exchanger. The role of mitochondria in the regulation of Ca²⁺ cycle has received much attention recently, as it is a central stage in neuronal survival and death processes. Over the last decades, the 4,1-benzothiazepine CGP37157 has been the only available blocker of the mitochondrial sodium/calcium exchanger, although it targets several other calcium transporters. We report the synthesis of 4,1-benzothiazepine derivatives with the goal of enhancing mitochondrial sodium/calcium exchanger blockade and selectivity, and the evaluation of their cytoprotective effect. The compound 4c presented an interesting neuroprotective profile in addition to an important blockade of the mitochondrial sodium/calcium exchanger. The use of this benzothiazepine could help to understand the physiological functions of the mitochondrial sodium/calcium exchanger. In addition, we hypothesize that a moderate blockade of the mitochondrial sodium/calcium exchanger would provide enhanced neuroprotection in neurons.