Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams).
A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexahydro-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 (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 epsilon-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 delta-valero-lactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.
Reddy
P A
PA
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Woodward
K E
KE
McIlheran
S M
SM
Hsiang
B C
BC
Latifi
T N
TN
Hill
M W
MW
Rothman
S M
SM
Ferrendelli
J A
JA
Covey
D F
DF
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002209:Caprolactam / Q000138:chemical synthesis* / Q000494:pharmacology; D004594:Electrophysiology; D005013:Ethosuximide / Q000494:pharmacology; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010881:Piperidones; D005013:Ethosuximide; D014635:Valproic Acid; D002209:Caprolactam; C037476:tert-butylbicyclophosphorothionate; C043384:2-piperidone; D010634:Phenobarbital