5-ARYL-3-(ALKYLTHIO)-4H-1,2,4-TRIAZOLES AS SELECTIVE ANTAGONISTS OF STRYCHNINE-INDUCED CONVULSIONS AND POTENTIAL ANTISPASTIC AGENTS

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-,a,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-fluorpphenyl)-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-,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-triazoles (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 [H-3]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated Cl-36 influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABA(A) receptor.