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 se...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1997-01, Vol.40 (1), p.44-49
Main Authors: Reddy, P. Amruta, Woodward, Karen E, McIlheran, Sarah M, Hsiang, Bonnie C. H, Latifi, Tammy N, Hill, Matthew W, Rothman, Steven M, Ferrendelli, James A, Covey, Douglas F
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - chemical synthesis
Anticonvulsants - pharmacology
Anticonvulsants. Antiepileptics. Antiparkinson agents
Biological and medical sciences
Bridged Bicyclo Compounds, Heterocyclic - metabolism
Caprolactam - chemical synthesis
Caprolactam - pharmacology
Electrophysiology
Ethosuximide - pharmacology
Medical sciences
Mice
Neuropharmacology
Pharmacology. Drug treatments
Phenobarbital - pharmacology
Piperidones - chemical synthesis
Piperidones - pharmacology
Rats
Valproic Acid - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm960561u