5 research outputs found
Comparative effects of three 1,4-dihydropyridine derivatives [OSI-1210, OSI-1211 (etaftoron), and OSI-3802] on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers: Relevance to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring
The 1,4-dihydropyridines OSI-1210, OSI-1211 (etaftoron), and OSI-3802 are compounds with similar chemical structure. They differ by the length of the alkoxyl chain in positions 3 and 5 of the dihydropyridine (DHP) ring and by their pharmacological action characteristics. However, as far as we know, a clear relationship between the effects of these compounds and the length of the alkoxyl chain in positions 3 and 5 of the DHP has not been established. The goal of this study was to compare the influence of OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers, correlating their actions with the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. Using either glutamate/malate or succinate as respiratory substrates, all the compounds, in concentrations of up to 500Â [mu]M, depressed state 3 and uncoupled respiration, respiratory control (RCR) and ADP/O ratios, and phosphorylation rate, whereas state 4 respiration was stimulated. However, the stimulatory effect on state 4 induced by OSI-3802, the compound with the longest chain in positions 3 and 5 of the DHP ring, as well as its inhibitory effects on RCR and ADP/O ratios and phosphorylation rate were more pronounced than that induced by OSI-1210 and OSI-1211 (etaftoron), the compounds with the shortest and intermediate chains, respectively. Moreover, OSI-3802 maximized state 4 stimulation and minimized RCR and ADP/O ratios, and phosphorylation rate at a concentration of 100Â [mu]M, whereas low graduate effects were detected with OSI-1210 and OSI-1211 (etaftoron) for concentrations of up to 500Â [mu]M. At low concentrations (<=30Â [mu]M), OSI-3802, like its analogue OSI-1212 (cerebrocrast), reduced the phase transition temperature, the cooperative unit size, and the enthalpy associated with the phase transition temperature of dimyristoylphosphatidylcholine (DMPC) membrane bilayers. A good correlation was established between the effects of 200Â [mu]M OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on glutamate/malate- and succinate-dependent RCR of rat liver mitochondria and on the enthalpy change ([Delta]H) for the thermotropic profile of DMPC membrane bilayers at a 0.2 drug/DMPC molar ratio, indicating that the changes induced by these compounds on both mitochondrial membrane integrity and physical properties of DMPC membrane bilayers are strongly related to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. A putative relationship between membrane physical perturbation, bioenergetics impairment and the molecular characteristics of the compounds will be established as an approach to better understand their differentiated toxicological and pharmacological actions.http://www.sciencedirect.com/science/article/B6T56-4S2F5R5-1/1/d46d9b162019efe8123b16f3b8eaec9
Synthesis and Studies of Calcium Channel Blocking and Antioxidant Activities of Novel 4-Pyridinium and/or N-Propargyl Substituted 1,4-Dihydropyridine Derivatives
The novel 1,4-DHP derivatives containing the cationic pyridine moiety at the position 4, and the N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle were designed, synthesised, and assessed in biological tests
Ecophysiological tolerance of duckweeds exposed to copper
http://www.sciencedirect.com/science/article/B6T4G-4TGXP9V-1/2/0652ab94eb95eab94ea56a82c424997
Toxicity of the herbicide linuron as assessed by bacterial and mitochondrial model systems
Synthesis and studies of calcium channel blocking and antioxidant activities of novel 4-pyridinium and/or N-propargyl substituted 1,4-dihydropyridine derivatives
The novel 1,4-dihydropyridine derivatives containing the cationic pyridine moiety at the
position 4, and the N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle
were designed, synthesised, and assessed in biological tests. Among all the novel
compounds, the 4-(N-dodecyl) pyridinium group-containing compounds 11 (without the
N-propargyl group) and 12 (with the N-propargyl group) demonstrated the highest
calcium antagonistic properties against neuroblastoma SH-SY5Y (IC50 about 5–14 mM)
and the vascular smooth muscle A7r5 cell (IC50 – 0.6–0.7 mM) lines, indicating that they
predominantly target the L-type calcium channels. These compounds showed a slight total
antioxidant activity. At concentrations close to those of L-type calcium channel blocking
ones, compound 12 did not affect mitochondrial functioning; also, no toxicity was
obtained in vivo. The N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle
did not essentially influence the compounds’ activity. The 4-(N-dodecyl) pyridinium
moiety-containing compounds can be considered as prototype molecules for further
chemical modifications and studies as cardioprotective/neuroprotective agents.This study was supported by ESF project No. 2009/
0217/1DP/1.1.1.2.0/09/APIA/VIAA/031; the EuroNanoMed
project ‘‘CheTherDel’’; Portuguese Research Council
(FCT), Faculty of Medicine, Centre for Neuroscience and
Cell Biology (CNC) and Marine and Environmental
Research Centre (IMAR–CMA) of the University of
Coimbra, Portugal