Jm. Kane et al., 5-ARYL-3-(ALKYLTHIO)-4H-1,2,4-TRIAZOLES AS SELECTIVE ANTAGONISTS OF STRYCHNINE-INDUCED CONVULSIONS AND POTENTIAL ANTISPASTIC AGENTS, Journal of medicinal chemistry, 37(1), 1994, pp. 125-132
Selected examples from three series of isomeric (alkylthio)-1,2,4-tria
zoles were prepared and examined for anticonvulsant activity versus st
rychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptop
ropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthi
o)-4H-,a,4-triazoles were selective antagonists of strychnine-induced
convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthi
o)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. Th
e most potent antagonist of strychnine-induced convulsions was pphenyl
)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selec
tive antagonist was 5-(3-fluorophenyl)4-methyl-3- (methylsulfonyl) -4H
-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-,2,4-tr
iazoles suggested that they were acting functionally like glycine rece
ptor agonists. Since it has recently been postulated that compounds po
ssessing glycine-agonist-like properties might be useful in the treatm
ent of spasticity, we examined nyl-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 spi
nal 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 vi
tro. On the other hand, 3c enhanced muscimol-stimulated Cl-36 influx i
n a rat cerebellar membrane preparation, indicating a possible interac
tion of these triazoles with the GABA(A) receptor.