EVIDENCE FOR A UNIQUE INTERACTION OF LORECLEZOLE WITH THE GABA RECEPTOR COMPLEX

The interaction of loreclezole (a structurally novel non-benzodiazepine anticonvulsant), diazepam, phenobarbital sodium, and ethosuximide with the benzodiazepine antagonists beta-CCE, Ro15-1788, and CGS 8216 and the purine antagonist aminophylline were examined in the rat i.v. metrazol seizure test. The anticonvulsant activity of loreclezole was inhibited by beta-CCE and CGS 8216 but not by Ro15-1788 or aminophylline. The inhibition produced by CGS 8216 was dose dependent (ID50 = 0.04 mg/kg i.p. CGS 8216) and surmountable. When the interactions of the various antagonists with loreclezole were compared to those of diazepam, phenobarbital sodium, and ethosuximide, a clear differentiation of activity was evident. Beta-CCE blocked the anticonvulsant activity of all four compounds whereas Ro15-1788 blocked only the anticonvulsant effects of diazepam. CGS 8216blocked the anticonvulsant effects of diazepam and loreclezole in a similar manner while being much less effective against the anticonvulsant effects of ethosuximide and ineffective against phenobarbital sodium. Aminophylline blocked the anticonvulsant effects of only ethosuximide. Based on these data and the anticonvulsant profile of loreclezole, we suggest that loreclezole represents a new class of agents which modulate GABAergic transmission via a unique interaction with the GABA receptor complex.