title: Syntheses and evaluation of anticonvulsant activity of novel branched alkyl carbamates.
abstract: A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl-carbamate (38) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED(50) = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED(50) = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy-safety profile and, consequently, are promising candidates for development as new antiepileptics.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Hen
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D013226:Status Epilepticus / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D002219:Carbamates