title: 5-Aryl-3-(alkylthio)-4H-1,2,4-triazoles as selective antagonists of strychnine-induced convulsions and potential antispastic agents.
abstract: Selected examples from three series of isomeric (alkylthio)-1,2,4-triazoles were prepared and examined for anticonvulsant activity versus strychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptopropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthio)-4H-1,2,4-triazoles were selective antagonists of strychnine-induced convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthio)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. The most potent antagonist of strychnine-induced convulsions was 5-(2-fluorophenyl)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selective antagonist was 5-(3-fluorophenyl)-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-1,2,4-triazoles suggested that they were acting functionally like glycine receptor agonists. Since it has recently been postulated that compounds possessing glycine-agonist-like properties might be useful in the treatment of spasticity, we examined 5-phenyl-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3c) in an in vivo model of spasticity. In this regard, 3c reduced the occurrence of hyperreflexia in rats that had received spinal transections 5-10 weeks previously. While triazole 3c appeared to possess glycine-agonist-like properties in vivo, it did not displace [3H]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated 36Cl influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABAA receptor.
authors.affiliation: Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
authors.forename: J M
authors.initials: JM
authors.lastname: Kane
authors.forename: M A
authors.initials: MA
authors.lastname: Staeger
authors.forename: C R
authors.initials: CR
authors.lastname: Dalton
authors.forename: F P
authors.initials: FP
authors.lastname: Miller
authors.forename: M W
authors.initials: MW
authors.lastname: Dudley
authors.forename: A M
authors.initials: AM
authors.lastname: Ogden
authors.forename: J H
authors.initials: JH
authors.lastname: Kehne
authors.forename: H J
authors.initials: HJ
authors.lastname: Ketteler
authors.forename: T C
authors.initials: TC
authors.lastname: McCloskey
authors.forename: Y
authors.initials: Y
authors.lastname: Senyah
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004597:Electroshock; D005442:Flumazenil / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009128:Muscle Spasticity / Q000188:drug therapy*; D010243:Paralysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D013329:Structure-Activity Relationship; D013331:Strychnine; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D002712:Chlorides; D014230:Triazoles; C077362:4-methyl-3-methylsulfonyl-5-phenyl-4H-1,2,4-triazole; D005442:Flumazenil; D013331:Strychnine