Effects of cannabinoids in membrane bilayers containing cholesterol

Mavromoustakos, Thomas; Daliani, I.

doi:10.1016/s0005-2736(99)00106-6

Cited by 25 publications

(13 citation statements)

References 33 publications

(31 reference statements)

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“…Furthermore, since MD analysis has been performed for both CB1 and CB2 receptors, results can be useful for synthetic chemists to produce more selective CB compounds. The localization of AMG3 at the binding sites of the CB1 and CB2 receptors are in the core region of TM3-TM7 in accordance with reported biophysical crystallographic and modelling studies [102][103][104][105][106][107][108][109][110][111][112][113][114][115] (Fig. 3).…”

Section: Strategy Applied For a System-iisupporting

confidence: 89%

Strategies in the Rational Drug Design

Mavromoustakos

Durdağı²,

Koukoulitsa³

et al. 2011

CMC

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Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.

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Section: Strategy Applied For a System-iisupporting

confidence: 89%

Strategies in the Rational Drug Design

Mavromoustakos

Durdağı²,

Koukoulitsa³

et al. 2011

CMC

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“…35 Furthermore, plasma membranes of mammalian cells are enriched with cholesterol, and cellular cholesterol depletion can disrupt certain cellular functions. 36 We, therefore, examined the role of membrane cholesterol for anandamide-induced apoptosis.…”

Section: Increased Level Of Anandamide In Serum Frommentioning

confidence: 99%

Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis

et al. 2003

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The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stressinduced hepatocyte damage. In this context, methyl-␤-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.

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“…Molecules possessing a phenolic hydroxyl group are localized in the interface of the lipid bilayers, with the phenolic hydroxyl group probably hydrogen-bonding either with the head-group or the glycerol carbonyls. The methylated analogs locate themselves deeper in the hydrophobic region since they lack the anchor for the polar region (Guo et al 2008;Martel et al 1993;Mavromoustakos et al 1991;1995a, b;1996a, b;1999;Sarpietro et al 2007, Yang et al 1993.…”

Section: Introductionmentioning

confidence: 99%

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

et al. 2011

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In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.

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Effects of cannabinoids in membrane bilayers containing cholesterol

Cited by 25 publications

References 33 publications

Strategies in the Rational Drug Design

Strategies in the Rational Drug Design

Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

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