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

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 beta-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 [11C]Ro 15-1788 as radioligand and positron emission tomography (PET) as a non-invasive technique to measure the binding of the [11C]benzodiazepine antagonist in brain, in vivo. The [11C]Ro 15-1788 bound in the brain could not be displaced by the administration of LY81067 but rather, the [11C]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.(ABSTRACT TRUNCATED AT 250 WORDS)