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This review summarises current knowledge about the genotoxic and genoprotective effects of 1,4-dihydropyridines (DHP) with the main focus on the water-soluble 1,4-DHPs. Most of these water-soluble compounds manifest very low calcium channel blocking activity, which is considered “unusual” for 1,4-DHPs. Glutapyrone, diludine, and AV-153 decrease spontaneous mutagenesis and frequency of mutations induced by chemical mutagens. AV-153, glutapyrone, and carbatones protect DNA against the damage produced by hydrogen peroxide, radiation, and peroxynitrite. The ability of these molecules to bind to the DNA may not be the only mechanism of DNA protection, as other mechanisms such as radical scavenging or binding to other genotoxic compounds may take place and enhance DNA repair. These uncertainties and reports of high 1,4-DHP concentrations damaging the DNA call for further in vitro and in vivo preclinical research, pharmacokinetic in particular, as it can help pinpoint the exact mechanism(s) of the genotoxic and/or genoprotective action of 1,4-DHPs.

The ubiquitin-proteasome system modifies different cellular and protein functions. Its dysregulation may lead to disrupted proteostasis associated with multiple pathologies and aging. Pharmacological regulation of proteasome functions is already an important part of the treatment of several diseases. 1,4-dihydropyridine (1,4-DHP) derivatives possess different pharmacological activities, including antiaging and neuroprotective. The aim of this study was to investigate the effects of several 1,4-DHP derivatives on mRNA expression levels of proteasomal genes Psma3, Psmb5, and Psmc6 in several organs of rats. Rats were treated with metcarbatone, etcarbatone, glutapyrone, styrylcarbatone, AV-153-Na, or AV-153-Ca per os for three days. mRNA expression levels were determined with real-time polymerase chain reaction (PCR). For AV-153-Na and AV-153-Ca, we also determined the expression of the Psma6 gene. In the kidney, metcarbatone, etcarbatone, styrylcarbatone, and AV-153-Na increased the expression of all analysed genes. Glutapyrone increased the expression of Psmb5 and Psmc6 but did not affect the expression of Psma3. In the blood, glutapyrone increased Psmb5 expression. In the liver, AV-153-Na increased the expression of Psma6 and Psmc6 but lowered the expression of Psmb5, while AV-153-Ca only increased Psma6 expression. The ability of 1,4-DHP derivatives to increase the expression of proteasome subunit genes might hold a therapeutic potential in conditions associated with impaired proteasomal functions, but further research is needed.

Cerebrocrast is a novel lipophilic dihydropyridine derivative with potential neuroprotective and antidiabetic properties. We have analyzed its interaction with L-type ([Ca.sub.V][1.2.sub.b]) and T-type ([Ca.sub.V]3.1) calcium channels using a wholecell patch clamp in HEK 293 cells. Cerebrocrast inhibited current flux through both [Ca.sub.V][1.2.sub.b] and [Ca.sub.V]3.1 channels. In both cases, the drug was about 10-fold less effective than neutral dihydropyridines, but more efficient than the charged dihydropyridine amlodipine. I[C.sub.50] values for the [Ca.sub.V][.sub.1.2b] channel were 586 ± 96 nmol/L and 178 ± 78 nmol/L at holding potentials of -80 mV and -50 mV, respectively. Approximately 50 mmol/L of cerebrocrast was needed to block 50% of the current amplitude in the [Ca.sub.V]3.1 channel, but this inhibition was not facilitated by shifting the holding potential from -100 mV to -70 mV. Cerebrocrast did not alter current kinetics in either investigated channel, and the inhibition of calcium current was partly reversible or irreversible. In conclusion, the interaction of cerebrocrast with [Ca.sub.V]3.1 lacked the typical characteristics of a state-dependent interaction, and voltage-dependent inhibition of [Ca.sub.V][1.2.sub.b] was consistent with partial interaction with the inactivated state of the channel. Key words: cerebrocrast, dihydropyridine, isradipine, nimodipine, calcium antagonist, L-type calcium channel, T-type calcium channel, state-dependent inhibition. Le cerebrocrast, un nouveau derive; lipophile des dihydropyridines, possede des proprieetes neuroprotectrices et antidiabetiques potentielles. Nous avons analyse son interaction avec les canaux calciques de type L ([Ca.sub.v][1.2.sub.b]) et de type T ([Ca.sub.v]3.1), en utilisant la technique de patch clamp de la cellule entiere dans des cellules HEC 293. Le cerebrocrast a inhibe le flux de courant par la voie des canaux [Ca.sub.v][1.2.sub.b] et [Ca.sub.v]3.1. Dans les deux cas, le medicament a ete d'un facteur dix moins efficace que les dihydropyridines neutres, mais plus efficace que la dihydropyridine chargee, amlodipine. Les valeurs d'I[C.sub.50] pour le canal [Ca.sub.v][1.2.sub.b] ont ete de 586 ± 96 nmol/L et de 178 ± 78 nmol/L aux potentiels de repos de -80 mV et de -50 mV respectivement. Environ 50 mmol/L de cerebrocrast ont ete necessaires pour bloquer 50 % de l'amplitude du courant dans le canal [Ca.sub.V]3.1, mais cette inhibition n'a pas ete faciliteeeen deplacant le potentiel de repos de -100 mV a -70 mV. Le cerebrocrast n'a pas modifie la cinetique du courant dans les deux canaux examines, et l'inhibition du courant calcique a ete partiellement reversible ou irreversible. En conclusion, l'interaction entre le cerebrocrast et les canaux [Ca.sub.v]3.1 n'a pas deemontre les caracteeristiques typiques d'une interaction dependante de l'etat d'ouverture du canal, et l'inhibition voltage dependante du canal [Ca.sub.v][1.2.sub.b] a montre une interaction partielle avec l'etat inactivee du canal. Mots-cles: cerebrocrast, dihydropyridine, isradipine, nimodipine, antagoniste calcique, canal calcique de type L, canal calcique de type T, inhibition dependante de l'etat. [Traduit par la Redaction] 10.1139/Y09-086, Introduction Cerebrocrast (4-(2-(difluoromethoxy)phenyl)-2,6-dimethyl 1,4-dihydropyridine-3,5-dicarboxylic acid di(2-propoxyethyl) diester) is a novel derivate of 1,4-dihydropyridines (DHPs) synthesized at the Latvian Institute of Organic Synthesis. Owing to its high lipophilicity, cerebrocrast easily penetrates [...]

Research has been conducted on the enantiomers of the cerebrocrast asymmetric analogue. The biological activities of these enantiomers have been investigated via the chemoenzymatic approaches using acyloxymethyl spacers and the relationship between the substrate structure and the enzymatic transformation rate has been studied.

We synthesized a set of 13 new and earlier described styrylpyridinium compounds (N‐alkyl styrylpyridinium salts with bromide or tosylate anions) in order to evaluate antifungal activity against C. albicans cells, to assay the possible synergism with fluconazole, and to estimate cytotoxicity to mammalian cells. All compounds were synthesized according to a well‐known two‐step procedure involving alkylation of γ‐picoline with appropriate alkyl bromide and further condensation with substituted benzaldehyde. Compounds with long N‐alkyl chains (C18H37–C20H41) had no antifungal activity against the cells of all tested C. albicans strains. Other styrylpyridinium compounds were able to inhibit yeast growth at the concentrations of 0.06–16 μg/ml. At fungicidal concentrations, the compound with the CN‐ group was least toxic to mammalian cells, showed the most effective synergism with fluconazole, and only slightly inhibited the respiration of C. albicans. The compound with the 4′‐diethylamino group exhibited the strongest fungicidal properties and effectively blocked the respiration of C. albicans cells. However, toxicity to mammalian cells was also high. Summarizing, the results of our study indicate that styrylpyridinium compounds are promising candidates in the development of new antifungal drugs. [ABSTRACT FROM AUTHOR]