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

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.

Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.