CLOBENPROPIT (VUF-9153), A NEW HISTAMINE H-3 RECEPTOR ANTAGONIST, INHIBITS ELECTRICALLY-INDUCED CONVULSIONS IN MICE

The effect of clobenpropit (VUF-9153), a new histamine H-3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H-3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H-1 receptor antagonist, but not by zolantidine, a histamine H-2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H-1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.