Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents.
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.
Woodard
P A
PA
Center for Drug Design and Delivery, University of Florida, J. Hillis Miller Health Center, Gainesville 32610.
Winwood
D
D
Brewster
M E
ME
Estes
K S
KS
Bodor
N
N
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects*; D004337:Drug Carriers; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D008566:Membranes / Q000187:drug effects; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D000927:Anticonvulsants; D004337:Drug Carriers; C068065:gamma-aminobutyric acid benzyl ester; D005680:gamma-Aminobutyric Acid