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.