U-54494A: a unique anticonvulsant related to kappa opioid agonists.

The benzamide U-54494A was compared to U-50488H (a structurally related kappa opioid agonist), phenytoin and phenobarbital in a variety of tests of anticonvulsant and sedative activities. In electroshock convulsion antagonism studies in mice and rats, U-54494A was generally similar to the standards in regard to milligrams of potency, threshold elevation, p.o. activity and duration of action. In contrast to phenytoin and phenobarbital, both U-54494A and U-50488H were effective antagonists of the convulsions induced by the excitatory amino acid agonists (kainic, N-methyl-aspartic and quisqualic acids) and the Ca++ channel agonist (Bay K 8644). They were not, however, effective antagonists of the gamma-aminobutyric acid-related convulsants (bicuculline and pentylenetetrazole), but all four blocked audiogenic convulsions in genetically epileptic mice. U-54494A in contrast to U-50488H lacks the kappa receptor-mediated sedative and analgesic activities but the anticonvulsant properties of both compounds are antagonized by high doses of naltrexone. Further investigations of the mechanism of action of these compounds revealed that both caused a dose-related suppression of post-tetanic repetitive discharge in cats soleus nerve-muscle preparations as measured by an abolition of the obligatory potentiation of soleus muscle contractile tension. On a biochemical level, both U-54494A and U-50488H attenuate the depolarization induced uptake of 45Ca++ into forebrain synaptosomes and block the enhancement of [3H]kainic acid binding induced by CaCl2. Together these results suggest that U-54494A is a unique and selective anticonvulsant agent acting by a Ca++-related mechanism possibly through a subclass of kappa receptors.