Article date: 1986/8/1
PubMed ID: 3016269
Journal name: Journal of medicinal chemistry (ISSN: 0022-2623)
Aromatic and heterocyclic esters of 1-methyl-4-piperidinol and 1,4-dimethyl-4-piperidinol and aromatic esters of (dialkylamino)alkanols were prepared and evaluated for antiepileptic activity by the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for minimal central neurotoxicity by the rotorod ataxia test. The most potent compound, namely the 2-phenylbenzoate (57) of 3-(diethylamino)propanol, was slightly more potent than diphenylhydantoin in the MES assay, while the 2-phenylbenzoate (24) of 1-methyl-4-piperidinol and the 2-phenylbenzoate (56) of (diethylamino)ethanol displayed activity comparable to that of diphenylhydantoin. The 2-phenethylbenzoate ester (6) of 1-methyl-4-piperidinol exhibited one-third the activity of diphenylhydantoin. The 2,4,5-trimethylbenzoate 40 and 2,4,6-trimethylbenzoate 41 of 1-methyl-4-pieridinol were even less potent, but did display activity in the phenobarbital-methsuximide range. Certain compounds interact with sites associated with the GABA receptor-chloride channel complex, but their potencies as anticonvulsant agents do not correlate with interaction at sites on the channel complex. Certain analogues antagonize binding of a batrachotoxin analogue to sodium channel sites, a property indicative of local anesthetic activity. There are structural similarities between 2-phenylbenzoates 57, 56, and 24 and diphenylhydantoin, and the latter anticonvulsant also antagonizes binding of the batrachotoxin analogue.
Author List: Waters J A, Hollingsworth E B, Daly J W, Lewandowski G, Creveling C R
Publication Types: Journal Article
Substances mentioned in the article: Amino Alcohols; Anticonvulsants; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Esters; Piperidines; Receptors, GABA-A; Muscimol; Phenytoin; tert-butylbicyclophosphorothionate; Diazepam; Pentylenetetrazole;
Mesh terms: Amino Alcohols/chemical synthesis; Animals; Anticonvulsants/chemical synthesis; Ataxia/drug therapy; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex/metabolism; Diazepam/metabolism; Electroshock; Esters; Muscimol/metabolism; Pentylenetetrazole; Phenytoin/therapeutic use; Piperidines/chemical synthesis; Rats; Receptors, GABA-A/metabolism; Structure-Activity Relationship;