Convulsant and anticonvulsant cyclopentanones and cyclohexanones

Area of Science:

• Neuroscience
• Pharmacology
• Organic Chemistry

Background:

• Cyclic ketones like cyclopentanone and cyclohexanone are investigated for their effects on the central nervous system.
• The picrotoxin receptor is a key target for understanding neuronal excitability and developing anticonvulsant or convulsant agents.

Purpose of the Study:

• To evaluate the convulsant and anticonvulsant properties of unsubstituted and alkyl-substituted cyclopentanones and cyclohexanones.
• To determine if these compounds interact with the picrotoxin receptor.
• To correlate structural modifications with neuroactivity and receptor binding.

Main Methods:

• Compounds were tested for their ability to induce seizures or inhibit pentylenetetrazol (PTZ)- and maximal electroshock (MES)-induced seizures in CF-1 mice.
• Binding assays were performed using [35S]t-butylbicyclophosphorothionate, a picrotoxin receptor ligand, with rat brain membranes.
• Structure-activity relationships were analyzed based on substituent position and size.

Main Results:

• Unsubstituted cyclopentanone and cyclohexanone exhibited anticonvulsant activity against both PTZ and MES seizures.
• Small alkyl substituents (≤2 carbons) generally maintained anticonvulsant effects, while larger substituents (≥3 carbons) often induced convulsions.
• All tested compounds displaced the picrotoxin receptor ligand, with convulsant compounds being more potent binders than anticonvulsants.

Conclusions:

• Cyclopentanone, cyclohexanone, and their alkyl-substituted derivatives modulate neuronal activity via the picrotoxin receptor.
• The position and size of alkyl substituents significantly influence the convulsant or anticonvulsant profile of these cyclic ketones.
• These compounds share a similar mechanism of action with neuroactive gamma-butyrolactones and gamma-thiobutyrolactones.