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Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents
P A Woodard1, D Winwood, M E Brewster
1Center for Drug Design and Delivery, University of Florida, J. Hillis Miller Health Center, Gainesville 32610.
Abstract:
A dihydropyridine in equilibrium with pyridinium salt redox system was applied to effect brain delivery of gamma-aminobutyric acid (GABA) derivatives and analogues. The redox system allows the lipophilic dihydropyridine conjugates to penetrate the blood brain barrier, whereas corresponding oxidized pyridinium forms are retained in the brain for an extended period and rapidly eliminated from the periphery. The most promising compound was the GABA benzyl ester-CDS (1a, Scheme I). It had an ED50 of 15.8 mg/kg (i.v.) in protecting mice against maximal electroconvulsive shock-induced tonic hind-leg extension.