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)

• Published in: Journal of medicinal chemistry Vol. 40; no. 1; pp. 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: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 03-01-1997
• 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; Nitrogen heterocycle; Toxicity; Rodentia; Lactam; Nervous system; Anticonvulsant; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Convulsion; Structure activity relation; Mouse; Animal; Six membered ring; Neurological disorder; Chemical synthesis; Seven membered ring
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960561u

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.