Benzothiazepine CGP37157and Its Isosteric 2′-MethylAnalogue Provide Neuroprotection and Block Cell Calcium Entry

摘要

Benzothiazepine is widely used as tool to explore the role of mitochondria in cell Ca²⁺ handling, by its blocking effect of the mitochondria Na⁺/Ca²⁺ exchanger. Recently, has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2′ of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3–30 μM, while only protected at 30 μM. Both compounds caused blockade of Ca²⁺ channels in high K⁺-depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervoussystem penetration (PAMPA-BBB; parallel artificial membrane permeabilityassay for blood-brain barrier) revealed that both compounds couldcross the blood–brain barrier, thus reaching their biologicaltargets in the central nervous system. In conclusion, by causing amild isosteric replacement in the benzothiazepine , we haveobtained ITH12505, with improved neuroprotective properties. Thesefindings may inspire the design and synthesis of new benzothiazepinestargeting mitochondrial Na⁺/Ca²⁺ exchanger andL-type voltage-dependent Ca²⁺ channels, having antioxidantproperties.