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ACS Chem Neurosci. 2012 Jul 18;3(7):519-29. doi: 10.1021/cn300009e. Epub 2012 Mar 26.

Benzothiazepine CGP37157 and its isosteric 2'-methyl analogue provide neuroprotection and block cell calcium entry.

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  • 1Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, C/Diego de León, 62, 28006 Madrid, Spain; Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispro Morcillo, 4, 28029, Madrid, Spain.


Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca(2+) handling, by its blocking effect of the mitochondria Na(+)/Ca(2+) exchanger. Recently, CGP37157 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 CGP37157 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, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3-30 μM, while CGP37157 only protected at 30 μM. Both compounds caused blockade of Ca(2+) channels in high K(+)-depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood-brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na(+)/Ca(2+) exchanger and L-type voltage-dependent Ca(2+) channels, having antioxidant properties.

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