| Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions. | |
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MedLine Citation:
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PMID: 9973186 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension, angina, and congestive heart failure. SB 211475 (4-[2-hydroxyl-3-[[2-(2-methoxyphenoxy)ethyl]amino]propoxyl]-9H-++ +carbazol-3-ol), a hydroxylated carvedilol analogue, is an even more potent antioxidant in several assay systems. Carvedilol also has neuroprotective capacity with modulatory actions at N-methyl-D-aspartate (NMDA) receptors and Na+ channels. In the present study, we demonstrated that in cultured rat cerebellar neurons, SB 211475 has 28-fold greater antioxidant activity than carvedilol, but is 2- to 6-fold less potent, respectively, at inhibiting neurotoxic activities at Na+ channels and at NMDA receptor channels. To determine a biophysical rationale for these differential activities, small angle x-ray scattering data were obtained from model lipid and brain membrane bilayers containing either carvedilol, SB 211475, or dihydropyridine calcium channel blockers. Electron density profiles revealed that the location of SB 211475 was restricted to the glycerol backbone/hydrocarbon interface and significantly reduced membrane width by 5%, whereas the time-averaged location for carvedilol and flunarizine also extended to the hydrated surface of the bilayer. Comparison of carvedilol with several dihydropyridines showed a correlation between high ClogP values (lipophilicity), Na+ channel inhibitory potency, and bilayer localization. The antioxidant activity of SB 211475 could be explained by restricted intercalation into the glycerol phosphate/hydrocarbon interface, creating an increase in volume associated with the phospholipid acyl chains, which would then become resistant to lipid peroxidation. Differential channel modulation may also be explained by these membrane structural results, which indicate that carvedilol and the less spatially restricted dihydropyridine molecules are more likely to inhibit transmembrane receptor channels. |
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Authors:
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P G Lysko; K A Lysko; C L Webb; G Feuerstein; P E Mason; M F Walter; R P Mason |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochemical pharmacology Volume: 56 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1998 Dec |
Date Detail:
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Created Date: 1999-02-12 Completed Date: 1999-02-12 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 1645-56 Citation Subset: IM |
Affiliation:
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Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA. Paul_G_Lysko@sbphrd.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antioxidants / pharmacology Calcium Channel Blockers / chemistry Carbazoles / chemistry, pharmacology* Cell Membrane / chemistry, drug effects* Cells, Cultured Cerebellum / chemistry Dihydropyridines / antagonists & inhibitors Free Radical Scavengers / pharmacology Lipid Bilayers / chemistry Models, Molecular Neurons / chemistry, drug effects* Neuroprotective Agents / pharmacology* Propanolamines / chemistry, pharmacology* Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate / drug effects Sodium Channel Blockers Veratridine / toxicity X-Ray Diffraction |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Calcium Channel Blockers; 0/Carbazoles; 0/Dihydropyridines; 0/Free Radical Scavengers; 0/Lipid Bilayers; 0/Neuroprotective Agents; 0/Propanolamines; 0/Receptors, N-Methyl-D-Aspartate; 0/Sodium Channel Blockers; 146574-43-8/SB 211475; 71-62-5/Veratridine; 72956-09-3/carvedilol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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