Synthesis and anticonvulsant activity of enaminones.
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.
Edafiogho
I O
IO
Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, D.C. 20059.
Hinko
C N
CN
Chang
H
H
Moore
J A
JA
Mulzac
D
D
Nicholson
J M
JM
Scott
K R
KR
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
D000588:Amines; D000927:Anticonvulsants