title: Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions.
abstract: 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.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA. Paul_G_Lysko@sbphrd.com
authors.forename: P G
authors.initials: PG
authors.lastname: Lysko
authors.forename: K A
authors.initials: KA
authors.lastname: Lysko
authors.forename: C L
authors.initials: CL
authors.lastname: Webb
authors.forename: G
authors.initials: G
authors.lastname: Feuerstein
authors.forename: P E
authors.initials: PE
authors.lastname: Mason
authors.forename: M F
authors.initials: MF
authors.lastname: Walter
authors.forename: R P
authors.initials: RP
authors.lastname: Mason
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D000077261:Carvedilol; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000737:chemistry; D004095:Dihydropyridines / Q000037:antagonists & inhibitors; D016166:Free Radical Scavengers / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry; D008958:Models, Molecular; D009474:Neurons / Q000737:chemistry / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D026941:Sodium Channel Blockers; D014701:Veratridine / Q000633:toxicity; D014961:X-Ray Diffraction