Anticonvulsant activity of the diaryltriazine, LY81067: studies using electroencephalographic recording and positron emission tomography.

Abstract It is reported that LY81067, a new diaryltriazine, possesses anticonvulsant properties against grand mal status epilepticus induced by intravenous administration of picrotoxin binding site ligands (Ro 5-4864 and pentylenetetrazole) in the baboon. Intravenous administration of LY81067 during the seizures blocked grand mal type electroencephalographic (EEG) paroxysmal discharges and led to a long electrical silence, progressively replaced by spike-and-wave discharges of low frequency (2 c/sec). A transient blocking effect was also observed when LY81067 was injected during grand mal status epilepticus induced by the benzodiazepine inverse agonist methyl β-carboline-3-carboxylate; however, the long electrical silence observed after administration of LY81067 was rapidly followed by grand mal type paroxysmal discharges in the EEG, which could be stopped by a subsequent injection of Ro 15-1788. However, LY81067 also displayed intrinsic epileptogenic properties. Administration of this drug alone led to the appearance of rhythmic EEG (2-3 c/sec) associated with myoclonia. Concomitantly with the EEG studies, interactions of all these drugs with benzodiazepine receptors were observed in vivo using [ 11 C]Ro 15-1788 as radioligand and positron emission tomography (PET) as a non-invasive technique to measure the binding of the [ 11 C]benzodiazepine antagonist in brain, in vivo . The [ 11 C]Ro 15-1788 bound in the brain could not be displaced by the administration of LY81067 but rather, the [ 11 C]antagonist binding in the brain was somewhat enhanced. Administration of pentylenetetrazole or Ro 5-4864 decreased the rate of wash-out of the radioligand. This fast effect of these two convulsant drugs was partially inhibited by the subsequent administration of LY81067. The concomitant blocking of the grand mal status epilepticus was also observed. Although LY81067 displayed epileptogenic properties when injected alone, the primarily anticonvulsant activity of this substance was reflected by its ability to counteract the effects of convulsant drugs on both the EEG activity and the kinetics of [ 11 C]Ro 15-1788 in brain. These concomitant PET and EEG studies suggest that in vivo benzodiazepine receptors do not mediate the anticonvulsant activity of LY81067. The potency of the latter may involve a “depressant” site close to the [ 35 S ]t- butylbicyclophosphorothionate binding site of the receptor complex.