Anticonvulsant activity of caramiphen analogs

Caramiphen potently blocks maximal electroshock (MES)-induced seizures in mice and rats. The anticonvulsant mechanism has been hypothesized to be due to high-affinity binding to sigma recognition sites in brain. To study the structure-activity relationship for anticonvulsant activity of caramiphen we evaluated 8 analogs in MES-induced seizures in rats and also determined whether a correlation exists between anticonvulsant potency and sigma binding affinity. Some of the analogs potently inhibited sigma binding but were devoid of anticonvulsant activity. Aminocaramiphen 2 (ED50 = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylcyclopentanecarboxylate 9 (ED50 = 4.8 mg/kg) showed anticonvulsant activity comparable to caramiphen (ED50 = 3.1 mg/kg), although in sigma binding assays the affinities were 3-and 30-fold less than caramiphen, respectively. In the presence of 250 microM of phenytoin, caramiphen and p-aminocaramiphen showed 3- to 5-fold increases in affinity for [3H](+)pentazocine binding, whereas piodocaramiphen, which was inactive as an anticonvulsant, showed no change in affinity for sigma binding. These results indicate that anticonvulsant activity of the caramiphen analogs is not due to interaction with sigma binding sites.