Targeting γ-aminobutyric acid (GABA) carriers to the brain: potential relevance as antiepileptic pro-drugs.
The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured.
Semreen
Mohammad H
MH
College of Pharmacy, University of Sharjah, Sharjah-27272, UAE. msemreen@sharjah.ac.ae
El-Shorbagi
Abdel-Nasser
AN
Al-Tel
Taleb H
TH
Alsalahat
Izzeddin M M
IM
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D018755:GABA Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D023421:Models, Animal; D010433:Pentylenetetrazole / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D005680:gamma-Aminobutyric Acid
D018755:GABA Agonists; D011355:Prodrugs; D013843:Thiazines; D013871:Thiones; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole