Ann C. McKeon

Anterior thalamus and substantia nigra: two distinct structures mediating experimental generalized seizures

Injection of gamma-vinyl aminobutyric acid (GVG) into the anterior thalamus protected rats against pentylenetetrazol (PTZ) seizures but not against maximal electroshock (MES) seizures. Injection of GVG into the substantia nigra protected against MES seizures but not against PTZ seizures. Both types of seizures were prevented by injections into both of the above brain regions. These data indicate that separate neuronal circuits mediate PTZ and MES seizures.

Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents.

Summary: Anticonvulsant properties of compounds that enhance GABA‐mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), α‐ethyl‐α‐methyl‐γ‐thiobutyrolactone (α‐EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro 15‐ 1788 and a‐isopropyl‐α‐methyl‐γ‐butyrolactone γ‐IMGBL)] and to 4,5,6,7‐tetrahy‐droisoxazolo‐[4,5‐c]‐pyridin‐3‐ol (THIP, GABAA receptor agonist), (±) baclofen (GABAB receptor agonist), and γ‐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‐dirnethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), bicuculline (BIC), aminophylline, strychnine, and τ‐butyl‐bicyclophosphorothionate (TBPS) in mice. CZP blocked all but strychnine seizures. PB was also highly effective, blocking all but TBPS seizures. α‐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. Rol S‐1788 and α‐IMGBL prevented only DMCM‐ and pentylenetetrazol (PTZ)‐induced seizures, respectively. THIP and γ‐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.

Structure-activity studies of fluoroaljyl-substituted γ-butyrolactone and γ-thiobutyrolactone modulators of GABAA receptor function

Dihydro-2(3H)-furanones (γ-butyrolactones) and dihydro-2(3H)-thiophenones (γ-thiobutyrolactones) containing fluoroalkyl groups at positions C-3, C-4, and C-5 of the heterocyclic rings were prepared. The anticonvulsant/convulsant activities of the compounds were evaluated in mice. Brain concentrations of the compounds were determined and the effects of the compounds on [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to the picrotoxin site on GABAA receptors were investigated. The effects of the compounds on GABAA receptor function were studied using electrophysiological methods and cultured rat hippocampal neurons. Fluorination at C-3 results in either subtle or pronounced effects on the pharmacological activity of the compounds. When hydrogen are replaced with fluorines at the methylene carbon of an ethyl groups, as in 3-(1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone (1), the anticonvulsant actions of the compound are not much changed from those found for the corresponding alkyl-substituted analogue. In marked contrast, fluorination and the methyl carbon of the ethyl group, as in dihydro-3-methyl-3-(2,2,2-trifluoroethyl)-2(3H)-furanone (3), produces a compound having convulsant activity. This convulsant activity seems to be due to an increased affinity of the compound for the picrotoxin site on GABAA receptors caused by an interaction that involves the trifluoromethyl group. Results obtained with γ-butyrolactones containing either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoromethyl)ethyl substitutent indicate that the interactions of the trifluoromethyl group with the picrotoxin binding site are subject to both stereochemical and steric constraints. Sulfur for oxygen heteroatom substitution, as in the corresponding γ-thiobutyrolactones, affects the type (competitive, non-competitive, etc.) of binding interactions that these compounds have with the picrotoxin site in a complex manner. Fluorination of alkyl groups at the C-4 and C-5 positions of γ-butyrolactones having convulsant activity increases convulsant potency.

Comparison of the Anticonvulsant Activities of Ethosuximide, Valproate, and a New Anticonvulsant, Thiobutyrolactone

Summary: Anticonvulsant properties of α‐ethyl‐α‐methyl–γ‐thiobutyrolactone (α‐EMTBL) were compared with those of the antiepileptic drugs ethosuximide (ESM) and valproate (VPA) by testing their ability to block seizures in mice caused by maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin (PICRO), bicuculline (BIC), methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), N‐methyl‐D,L‐aspartate (NMDA), aminophylline (AMPH), strychnine (STR), β‐ethyl‐β‐methyl‐γ‐thiobutyrolactone (P‐EMTBL), and t‐butylbicyclophosphorothionate (TBPS). ESM was able to prevent PTZ‐, PICRO‐, DMCM‐, and β‐EMTBL‐induced seizures. In contrast, VPA and α‐EMTBL blocked all of these plus MES‐, TBPS‐, and BIC‐induced convulsions. Only VPA prevented AMPH‐induced seizures. None of the anticonvulsants blocked STR or NMD A seizures. Rotorod testing for acute neurotoxicity demonstrated that ESM was the least toxic and α‐EMTBL and VPA were equivalent. Animals treated daily with high doses of α‐EMTBL for a 2‐week period appeared healthier and had a higher survival rate than animals treated with VPA in the same manner. After a single intraperitoneal (i.p.) injection, the duration of anticonvulsant action of α‐EMTBL was 1.3 and 4 times longer than that of ESM and VPA, respectively. These results indicate that α‐EMTBL has a wide spectrum of anticonvulsant action like VPA but may be less toxic and longer acting. We suggest that α‐EMTBL is a compound worthy of further testing and development as an antiepileptic drug (AED).

Effects of alkyl-substituted γ-butyrolactones and succinimides on the evoked and spontaneous activity of hippocampal slices in vitro

Alkyl-substituted and unsubstituted derivatives of gamma-butyrolactone (GBL), gamma-hydroxybutyrate (GHB), and succinimide were tested for their effects on the evoked potential (EP) and spontaneous activity of hippocampal slices incubated in vitro. When tested alone, only beta-ethyl-beta-methyl-GBL (beta-EMGBL) and tetramethylsuccinimide (TMSM) had any effect, producing greatly augmented EPs and spontaneous epileptiform discharges. The nonexcitatory drugs were also tested for the ability to block the excitation produced by beta-EMGBL, TMSM, and penicillin. The unsubstituted compounds had no effect on the augmented EP induced by any of the convulsants. The alpha-ethyl-alpha-methyl-substituted GBL (alpha-EMGBL) and ethosuximide (ESM), blocked the augmented EP induced by beta-EMGBL and TMSM but not that induced by penicillin. The spontaneous activity induced by all three excitatory agents was blocked by GHB. Unsubstituted succinimide had no effect on spontaneous activity. The spontaneous activity produced by beta-EMGBL and TMSM was blocked by alpha-EMGBL, but ESM blocked only that induced by TMSM. Neither alpha-EMGBL nor ESM blocked the spontaneous activity produced by penicillin. We conclude that the ability to block the EP more closely parallels in vivo anticonvulsant activity whereas effects on the spontaneous activity may be more related to neuronal depressant effects. The alkyl-substituted GBLs and succinimides had very similar, albeit not identical, effects on incubated hippocampal slices. That may indicate that they have a similar but not a common mechanism of action.