Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3- benzyl-2-piperidinones (δ-valerolactams) and hexahydro-2H-azepin-2-ones (ε- caprolactams)

A series of 3-substituted 2-piperidinone (δ-valerolactam) and hexahydro-2H-azepin-2-one (ε-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 (ED₅₀, 37 mg/kg; PI (TD₅₀/ED₅₀), 4.46), and 3-benzyl compound 4c (ED₅₀, 41 mg/kg; PI, 7.05) is the most effective anticonvulsant against seizures induced by maximal electroshock. By contrast, none of the ε-caprolactams tested had anticonvulsant effects below doses causing rotorod toxicity. log P values were correlated with neurotoxicity and [³⁵S]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the δ-valerolactams and ε-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.