title: Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents.
abstract: Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro15-1788 and alpha-isopropyl-alpha-methyl-gamma-butyrolactone gamma-IMGBL)] and to 4,5,6,7-tetrahydroisoxazolo-[4,5-c]-pyridin-3-ol (THIP, GABAA receptor agonist), (+/-) baclofen (GABAB receptor agonist), and gamma-vinyl GABA, a compound that increases endogenous GABA. The compounds were tested for their ability to block experimental seizures caused by maximal electroshock, pentylenetetrazol, picrotoxin, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), bicuculline (BIC), aminophylline, strychnine, and t-butyl-bicyclophosphorothionate (TBPS) in mice. CZP blocked all but strychnine seizures. PB was also highly effective, blocking all but TBPS seizures. alpha-EMTBL, representing a new class of experimental anticonvulsant drugs, prevented all seizures except strychnine (STR)- and aminophylline-induced seizures. The antagonists are effective only against one convulsant stimulus. Ro15-1788 and alpha-IMGBL prevented only DMCM- and pentylenetetrazol (PTZ)-induced seizures, respectively. THIP and gamma-vinyl GABA both blocked only BIC and picrotoxin seizures. Baclofen had no anticonvulsant activity. These data demonstrate that compounds that increase neuronal inhibition by potentiating the action of GABA have a broader spectrum of anticonvulsant action than either antagonists or GABAmimetic agents or compounds that increase endogenous GABA.
authors.affiliation: Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: K D
authors.initials: KD
authors.lastname: Holland
authors.forename: A C
authors.initials: AC
authors.lastname: McKeon
authors.forename: D J
authors.initials: DJ
authors.lastname: Canney
authors.forename: D F
authors.initials: DF
authors.lastname: Covey
authors.forename: J A
authors.initials: JA
authors.lastname: Ferrendelli
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D000614:Aminocaproates / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001418:Baclofen / Q000494:pharmacology / Q000633:toxicity; D001463:Barbiturates / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002712:Chlorides / Q000502:physiology; D002998:Clonazepam / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D005442:Flumazenil / Q000494:pharmacology / Q000633:toxicity; D007476:Ionophores; D007555:Isoxazoles / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology / Q000633:toxicity; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D020888:Vigabatrin
chemical_list: D015107:4-Butyrolactone; D000614:Aminocaproates; D000927:Anticonvulsants; D001418:Baclofen; D001463:Barbiturates; D001569:Benzodiazepines; D002712:Chlorides; D002998:Clonazepam; D005442:Flumazenil; D007476:Ionophores; D007555:Isoxazoles; D010634:Phenobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; D020888:Vigabatrin; C062606:GABA-benzodiazepine receptor-chloride ionophore complex; C051894:alpha-ethyl, alpha-methyl-thiobutyrolactone; C066811:alpha-isopropyl-alpha-methyl-gamma-butyrolactone; C015542:gaboxadol