ANTICONVULSANT AND RELATED EFFECTS OF U-54494A IN VARIOUS SEIZURE TESTS

The anticonvulsant activity of methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl ]-benzamide monohydrochloride (U-54494A), a benzamide derivative chemi cally related to kappa opioid receptor agonists, was investigated in t hree selected seizure models of experimental epilepsy. In the maximal electroshock seizure test in mice, U-54494A (ED50 28 mg/kg i.p.) was e ffective, with a potency somewhat less than phenobarbital. In combinat ion with clinically used antiepileptics, especially phenobarbital and carbamazepine, the anticonvulsant activity of the latter was significa ntly increased. More detailed studies with phenobarbital showed additi ve anticonvulsant effects. The anticonvulsant activity of U-54494A was partially antagonized by naloxone. On the other hand, this compound d id not elevate the pentylenetetrazol seizure threshold (at high doses a tendency of proconvulsant action was seen). Furthermore, in unrestra ined rats with chronically implanted electrodes, U-54494A (greater-tha n-or-equal-to 10 mg/kg) significantly reduced the duration of electric ally evoked hippocampal afterdischarges. However, the focal stimulatio n threshold was not markedly increased. With respect to the possible m ode of action, whole-cell voltage-clamp experiments on cultured neonat al rat cardiomyocytes showed that U-54494A depressed the fast sodium i nward current in a concentration- and frequency-dependent manner. In s ummary, our results agree with earlier reports that demonstrated marke d anticonvulsant effects of U-54494A in grand mal-analogous seizure te sts. Moreover, in combination with some standard antiepileptics, addit ive effects can be found. It is suggested that, in addition to kappa o pioid and excitatory amino acid receptor related effects, modulations of Na+ membrane currents may contribute to the mechanisms of action.