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)

P. Amruta Reddy, Karen E. Woodward, Sarah M. McIlheran, Bonnie C.H. Hsiang, Tammy N. Latifi, Matthew W. Hill, Steven M. Rothman, James A. Ferrendelli, Douglas F. Covey

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Abstract

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.

Original languageEnglish
Pages (from-to)44-49
Number of pages6
JournalJournal of Medicinal Chemistry
Volume40
Issue number1
DOIs
StatePublished - Jan 3 1997

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