title: Synthesis and anticonvulsant activity of enaminones.
abstract: A new series of novel enaminones has been synthesized from cyclic beta-dicarbonyl precursors which were condensed with morpholine, pyrrolidine, phenethylamine, hydrazines, substituted benzyl amines, and substituted anilines. These compounds were subsequently evaluated for anticonvulsant activity in a variety of anticonvulsant models by the National Institute of Neurological and Communicative Disorders and Stroke and in our laboratory. Several of these compounds exhibited potent anticonvulsant activity with a remarkable lack of neurotoxicity. The most active analog, methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en-1-oate++ + (27), was protective in the maximal electroshock (MES) seizure test in the rat with an oral ED50 of 5.8 mg/kg with no toxicity noted at doses up to 380 mg/kg, thus providing a protective index (TD50/ED50) of greater than 65.5. A similar protective index for 27 was noted upon intraperitoneal (ip) administration in mice. The anticonvulsant effect of 27 occurred within 15 min of administration and the compound remained active beyond 4 h. Compound 27 was also active in the rat corneal kindled model. The application of Free-Wilson analysis to structure-activity correlation in this series is discussed.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, D.C. 20059.
authors.forename: I O
authors.initials: IO
authors.lastname: Edafiogho
authors.forename: C N
authors.initials: CN
authors.lastname: Hinko
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.forename: J A
authors.initials: JA
authors.lastname: Moore
authors.forename: D
authors.initials: D
authors.lastname: Mulzac
authors.forename: J M
authors.initials: JM
authors.lastname: Nicholson
authors.forename: K R
authors.initials: KR
authors.lastname: Scott
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D007696:Kindling, Neurologic; D008297:Male; D051379:Mice; D051381:Rats; D012640:Seizures / Q000209:etiology; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000927:Anticonvulsants