SYNTHESIS AND ANTICONVULSANT ACTIVITY OF ENAMINONES .2. FURTHER STRUCTURE-ACTIVITY CORRELATIONS

This report continues the in-depth evaluation of methyl ophenyl)amino] -6-methyl-2-oxocyclohex-3-en-1-oate, 1 (ADD 196022), and methyl benzyl amino)-6-methyl-2-oxocyclohex-3-en-1-oate,2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kin dling model. Neither 1 nor 2 was active against amygdala kindled seizu res, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Addit ional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to mini mizing toxicity. In a special ip rat screen developed by the Antiepile ptic Drug Development (ADD) Program, these newer analogs were evaluate d for protection against maximal electroshock seizures (MES) at 10 mg/ kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl ophe nyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a pro tective index (TD50/ED50) of >67. By variation in the ring size, addit ional aromatic substitutions and the synthesis of acyclic analogs, the se newer compounds provide a more definitive insight into the structur e-activity correlation. CLOGP evaluation and molecular modeling studie s are also provided to further elaborate the molecular characteristics of potential anticonvulsant