Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

Abstract

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.

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

“…Therefore, we carry out a more physiological model of biological evaluation, defined by the use of rat hippocampal slices subjected to toxic stimuli related to AD, recording the ability of selected compounds to counteract the tissue damage. 17,50,63,80 In this preparation, neurons are surrounded by their natural environment, e.g. glia cells, extracellular matrix, etc.…”

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

“…SH-SY5Y cells were seeded, subcultured, and treated similarly to what was previously described. 34 Neuronal Viability Experiments in Rat Hippocampal Slices Stressed with Glutamate. Experiments were performed in hippocampal slices prepared from brains of 2-month-old Sprague−Dawley rats (275−325 g weight), following the European Union Council Directive issued for these purposes and were approved by the Ethics Committee of the Facultad de Medicina, Universidad Autońoma de Madrid, Spain.…”

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

“…3B and 3C). This increase in cell survival could be attributed to the blocking action of CGP37157 on NMDAR, VDCCs, and NCX, preventing the Ca 2+ overload upon exposure to ischemic conditions [22]. Moreover, CGP37157 (30 µM) was neuroprotective in the OGD/Reox protocol in Calhm1 +/+ slices ( Figure 3D), but not in Calhm1 −/− mice ( Figure 3E).…”

“…The addition of the CGP37157 (10 µM) to the medium during the glutamate incubation period increased cell viability significantly in hippocampal slices from Calhm1 +/+ mice, but it did not provide significant protection in Calhm1 −/− slices. The increase in cell survival in Calhm1 +/+ slices may be related to the blocking action on NMDAR, VDCCs and sodium calcium exchanger (NCX) reported for CGP37157, preventing the Ca 2+ overload upon exposure to high glutamate concentrations [22]. This effect is higher in Calhm1 +/+ slices because CGP37157 is also blocking Ca 2+ influx through CALHM1, which is not present in Calhm1 −/− slices ( Figure 2).…”

“…Mechanical thrombectomy complications occur in 11% of the patients and the intravenous thrombolytic treatment, using recombinant tissue exchanger located in the mitochondrial membrane and partially blocks voltage-gated Na + and L-type voltage-dependent calcium channels. This compound, which is able to cross the BBB, has been shown to exert neuroprotective properties in different oxidative stress models [22].…”