Comparative Anticonvulsant Activity and Neurotoxicity of 4‐Amino‐N‐(2,6‐dimethylphenyl) benzamide and Prototype Antiepileptic Drugs in Mice and Rats

Cr, Clark

doi:10.1111/j.1528-1157.1988.tb04420.x

Cited by 41 publications

(36 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The much lower ED50 values obtained for BDZs are comparable to those previously reported data against PTZ, PTX and BIC (Krall et al, 1978;Paul et al, 1979;Shenoy et al, 1982;Clark, 1988;Belellei et al, 1989;Swinyard et al, 1989;Von Voigtlander and Lewis, 1991;Holland et al, 1992). These observations indicate that benzodiazepines are highly effective against IPBP-, PTZ-, PTX-and BIC-induced seizures.…”

Section: Discussionsupporting

confidence: 93%

“…The anticonvulsant potency (EDs0 values) of phenobarbital and pentobarbital against IPBP are greater than 30 mg/kg in the present experiments. These EDs0 values are much greater than those against PTZ-and PTX-induced seizures, but are comparable to the EDs0 values against bicuculline (BIC) (Shenoy et al, 1982;Clark, 1988;Belellei et al, 1989;Holland et al, 1992). Previous studies have shown that the competitive GABA A receptor antagonist BIC reverses the noncompetitive inhibitory effects of phenobarbital and pentobarbital on TBPS binding (Squares et al, 1983;Holland et al, 1990).…”

Section: Discussionmentioning

confidence: 52%

See 1 more Smart Citation

Evaluation of motor toxicity and anticonvulsant efficacy of barbiturates and benzodiazepines in a bicyclophosphate seizure model in mice

Liu

Chen

2000

neurotox res

View full text Add to dashboard Cite

1. 2. 3. 4.4-Alkyl derivatives of 2,6,7-trioxa-l-phosphabicyclo [2.2.2] octane-I-oxide [Bicyclophosphates (BP)] are highly toxic convulsants and potent GABA A receptor antagonists.The effects of various clinical used anticonvulsant drugs, barbiturates and benzodiazepines, on motor performance and 4-isopropylbicyclophosphate (IPBP), a homologue of BP, induced myoclonic and generalized tonic-clonic seizures were investigated in mice.The anticonvulsant drugs were IP administered 30 min. prior to the inverted screen test, a measure of minimal neurological deficit, and were then challenged with a 97% convulsant dose of IPBP (0.15 mg/kg, SC).The results show that: 1) benzodiazepines are more likely to have favorable motor toxicity and anticonvulsant profiles than barbiturates. 2) Various doses of these drugs that did not significantly cause motor impairment increase the mean latencies to myoclonic and generalized tonic-clonic seizures.3) The increase in anticonvulsant activity is associated with a comparable The potential use of 45-0088-S and clonazepam in the treatment of BP-induced seizures should be explored further.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 52%

Evaluation of motor toxicity and anticonvulsant efficacy of barbiturates and benzodiazepines in a bicyclophosphate seizure model in mice

Liu

Chen

2000

neurotox res

View full text Add to dashboard Cite

show abstract

“…The present data reaffirm the potency and selectivity of ameltolide as an anticonvulsant in the MES test in rats and mice, as previously reported (Clark, 1988;Leander et al, 1988). The most important finding of the present study is that the log plasma concentrations of ameltolide are highly linearly related to log dose of ameltolide from the low dose/ plasma range at which the anticonvulsant effects occur and through the high dose/plasma range at which the neurologically impairing effects occur (Fig.…”

Section: Discussionsupporting

confidence: 93%

Relation of Plasma and Brain Concentrations of the Anticonvulsant Ameltolide to Its Pharmacologic Effects

Potts

et al. 1992

Epilepsia

View full text Add to dashboard Cite

Ameltolide, a newly described anticonvulsant, was studied to determine the relation between dose administered, plasma and brain concentrations, and pharmacologic effects. The relation of the N-acetyl metabolite and the OH-N-acetyl metabolite to the dose administered and to the pharmacologic effects was also determined. Ameltolide plasma concentrations in both mice and rats were linearly related to dose administered over the entire dose range from low doses, at which the anticonvulsant effects were noted, to high doses, at which neurologic impairment occurred. The plasma concentrations of the metabolites were not as consistently linearly dose-related in the two species. In rats, the brain concentrations of ameltolide were highly correlated with plasma concentrations and the doses administered. Ameltolide was shown to have a phenytoin (PHT)-like anticonvulsant profile in vitro in the cortical slice preparation. These data confirm the potent anticonvulsant profile of ameltolide and the lack of significant activity of the metabolites.

show abstract

“…Addition of a second ortho-methyl group reinforces this activity, which leads to the highly potent ameltolide (1), a compound developed by Eli Lilly (LY 201116), which exhibits a phenytoin-like profile. Ameltolide is very potent in the MES test, while it is inactive in the subcutaneous pentylenetetrazol (scPTZ) test (Clark, 1988). On a molar basis, 1 was found three times more active in the MES test than phenytoin (2) and carbamazepine (3), two well established standard antiepileptic drugs.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship of phenytoinergic antiepileptic drugs related to ameltolide

et al. 2007

View full text Add to dashboard Cite

Ameltolide shares with phenytoin and carbamazepine a common mode of action involving interaction with central voltage-dependent sodium channels. Ameltolide and structurally related benzanilides were subjected to molecular modeling studies using both molecular mechanics (MM2, Amber96, and OPLS) and semiempirical quantum mechanics (AM1, PM3, and PM3 Cosmo) to resolve a paradox: while compounds with a phenytoin-like pharmacological profile possess a CO-NH moiety in a cis-configuration, ameltolide was found via X-ray crystallography to exist in the trans-configuration. Results obtained both by molecular mechanics and semiempirical methods indicate that for ameltolide, the cis and trans forms have similar energy content. Additional ab initio calculations performed at 6-31G** gave a DE (Z -E) on the order of 3 kcal/mol. In view of this small energy difference between the cis and trans forms, it is conceivable that these benzanilides bind to their biological target in their cis configuration, therefore assuming a common structure-activity relationship with classical antiepileptic agents.

show abstract

Comparative Anticonvulsant Activity and Neurotoxicity of 4‐Amino‐N‐(2,6‐dimethylphenyl) benzamide and Prototype Antiepileptic Drugs in Mice and Rats

Cited by 41 publications

References 10 publications

Evaluation of motor toxicity and anticonvulsant efficacy of barbiturates and benzodiazepines in a bicyclophosphate seizure model in mice

Evaluation of motor toxicity and anticonvulsant efficacy of barbiturates and benzodiazepines in a bicyclophosphate seizure model in mice

Relation of Plasma and Brain Concentrations of the Anticonvulsant Ameltolide to Its Pharmacologic Effects

Structure–activity relationship of phenytoinergic antiepileptic drugs related to ameltolide

Contact Info

Product

Resources

About