Convulsant and anticonvulsant cyclopentanones and cyclohexanones.
The convulsant and/or anticonvulsant activity of unsubstituted and mono-alkyl-substituted cyclopentanones and cyclohexanones were examined by testing the ability of these compounds to produce seizures or to inhibit seizures induced by pentylenetetrazol and maximal electroshock in CF-1 mice. In addition, these compounds were tested for their ability to bind to the picrotoxin receptor. The unsubstituted compounds, cyclopentanone and cyclohexanone, prevented both pentylnetetrazol- and maximal electroshock-induced seizures. Cyclopentanones and cyclohexanones with small (less than 3 carbon atoms) alkyl substituents in the 2-position were also anticonvulsant; all of these compounds, except 2-ethylcyclohexanone, blocked both pentylenetrazol- and maximal electroshock-induced seizures. 2-Ethylcyclohexanone was very effective against pentylenetetrazol seizures but did not prevent maximal electroshock seizures. Cyclohexanones with larger alkyl substituents in the 2-position, 2-propylcyclohexanone and 2-t-butylcyclohexanone, caused clonic seizures following injection into mice. Of the cyclopentanones and cyclohexanones with alkyl substitutions in the 3-position that were studied, one was an anticonvulsant (3-methylcyclopentanone), one was a mixed convulsant/anticonvulsant (3-ethylcyclohexanone), and the other two (3-ethylcyclopentanone and 3-t-butylcyclohexanone) were convulsants. Finally, two cyclohexanones with alkyl substituents in the 4-position were studied. Both 4-ethylcyclohexanone and 4-t-butylcyclohexanone produced convulsions when injected into mice. All the neuroactive cyclopentanones and cyclohexanones competitively displaced [35S]t-butylbicyclophosphorothionate, a ligand specific for the picrotoxin receptor, from rat brain membranes. The convulsant compounds were generally more potent than the anticonvulsants. The cyclohexanones were more potent than their corresponding cyclopentanones and the binding potency of both increased as the size of the alkyl substituent increased. These results suggest that cyclopentanone, cyclohexanone, and their alkyl-substituted derivatives act at the picrotoxin receptor to increase or decrease neuronal activity. Thus, they appear to have sites and mechanisms of action similar to those of the neuroactive gamma-butyrolactones and gamma-thiobutyrolactones.
Holland
K D
KD
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Naritoku
D K
DK
McKeon
A C
AC
Ferrendelli
J A
JA
Covey
D F
DF
D000818:Animals; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002462:Cell Membrane / Q000378:metabolism; D003292:Convulsants; D003508:Cycloheptanes / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology*; D066298:In Vitro Techniques; D007659:Ketones; D007783:Lactones / Q000378:metabolism; D051379:Mice; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D003508:Cycloheptanes; D003517:Cyclopentanes; D007659:Ketones; D007783:Lactones; D011963:Receptors, GABA-A; C037480:picrotoxinin receptor; C007201:cyclopentanone; C037476:tert-butylbicyclophosphorothionate; C000363:cycloheptanone