SYNTHESIS AND ANTICONVULSANT ACTIVITIES OF 3,3-DIALKYL-3-BENZYL-2-PIPERIDINONE AND 3-ALKYL-3-BENZYL-2-PIPERIDINONE (DELTA-VALEROLACTAMS) AND HEXAHYDRO-2H-AZEPIN-2-ONES (EPSILON-CAPROLACTAMS)

A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexa hydro-2H-azepin-2-one (epsilon-caprolactam) derivatives were prepared and evaluated as anticonvulsants in mice. In the 2-piperidinone series , 3,3-diethyl compound 7b is the most effective anticonvulsant against pentylenetetrazole-induced seizures (ED(50), 37 mg/kg; PI (TD50/ED(50 )), 4.46), and 3-benzyl compound 4c (ED(50), 41 mg/kg; PI, 7.05) is th e most effective anticonvulsant against-seizures induced by maximal el ectroshock. By contrast, none of the epsilon-caprolactams tested had a nticonvulsant effects below doses causing rotorod toxicity. log P valu es were correlated with neurotoxicity and [S-35]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the delta-val erolactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat-hippocampal neurons.