ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia.

During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 µM) and veratridine in hippocampal slices (26% protection at 10 µM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 µM) and oxygen and glucose deprivation (76% protection at 10 µM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.

The effect of ionizing radiation of 1,4-dihydropyridine derivatives in the solid state.

Electron paramagnetic resonance (EPR) spectroscopy was used to investigate the gamma-radiation damage in the crystalline powder form of nine calcium channel blockers from the 1,4-dihydropyridine derivatives, which are in clinical use for treatment of arteria hypertension and ischemic heart disease. EPR studies have been carried out, showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals trapped. EPR spectra of isardipine and felodipine showed single EPR line. EPR spectra of nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine and nilvadipine reveal a broad anisotropic signal of hyperfine interaction. No EPR signal was observed from amlodipine.

Calcium antagonistic properties of the sesquiterpene T-cadinol and related substances: structure-activity studies.

The calcium antagonistic properties of (+)-T-cadinol, some of its stereoisomers and related terpenes were investigated in both functional and radioligand binding studies, and the effects were compared with those of the dihydropyridine calcium antagonist (+/-)-nimodipine. In the isolated rat aorta, the terpenes relaxed contractions induced by 60 mM K+ more potently than those induced by phenylephrine. (+)-T-cadinol and its stereoisomers were the most potent among the terpenes to relax K(+)-induced contractions, whereas they were approximately 10,000 times less potent than (+/-)-nimodipine in this regard. Binding of the dihydropyridine radioligand [3H]-(+)-PN200-110 was studied on rat cerebral cortical membranes. Displacement and saturation studies indicated that (+)-T-cadinol caused a competitive inhibition of binding. The log Ki values for (+)-T-cadinol and (+/-)-nimodipine from displacement studies (-4.7 and -9.2) corresponded with the log RC50 values for relaxation of K(+)-contracted rat aortas (-5.0 and -9.0). For the terpenes, there was a significant correlation (P < 0.001, rs = 0.89) between displacement of dihydropyridine binding and the ability to relax K(+)-induced contractions. The structures of three terpenes were chemically modified by blocking hydroxyl groups. The potency of these derivatives, as well as the naturally occurring derivative-2-oxo-T-cadinol, to relax K(+)-induced contractions was not correlated to the lipophilicity of the compounds. Instead, other qualities appear to be of importance for the functional effects.(ABSTRACT TRUNCATED AT 250 WORDS)