TRIAZOLINES .26. 1-ARYL-5-AMIDO-1,2,3-TRIAZOLINES, A NEW GROUP OF TRIAZOLINE ANTICONVULSANTS - EFFECT OF 5-SUBSTITUTION ON ANTICONVULSANT ACTIVITY

Studies in our laboratories have led to the discovery of the Delta(2)- 1,2,3-triazolines as a unique family of anticonvulsant agents hitherto unknown. The anticonvulsant activity of 1,5-diaryl- and 1-aryl-5-pyri dyltriazolines was previously reported; this paper describes the evalu ation of two series of 1-aryl-5-amido-1,2,3-triazolines, A and B, wher e the 5-amido groups are (2-oxo-1-pyrrolidino)- (1-8) and (N-methyl-N- acetamido)- (9-15), respectively. The 1-aryl-5-(2-oxo-1-pyrrolidino)-1 ,2,3-triazolines of the A series, which are uniquely substituted with the pyrrolidinone lactam ring, a cyclic gamma-aminobutyric acid (GABA) structure, seem to function by enhancing inhibitory GABAergic mechani sms. Radioligand binding studies for the two most active triazolines 2 and 7, indicate that both compounds strongly inhibit the specific bin ding of [H-3]GABA to GABA(B) receptor sites, with K-i = 1.7 and 0.91 m u M respectively. The anticonvulsant activity among the various groups of triazolines studied so far appears to be dependent on the 5-substi tuent groups : 4-pyridyl- much greater than 2-oxo-1-pyrrolidino- > N-m ethyl-N-acetamido- > 3-pyridyl greater than or equal to aryl - 2-pyrid yl > 2-quinolyl.