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 acti vity of caramiphen we evaluated 8 analogs in MES-induced seizures in r ats and also determined whether a correlation exists between anticonvu lsant potency and a binding affinity. Some of the analogs potently inh ibited sigma binding but were devoid of anticonvulsant activity. Amino caramiphen 2 (ED(50) = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylc yclopentanecarboxylate 9 (ED(50) = 4.8 mg/kg) showed anticonvulsant ac tivity comparable to caramiphen (ED(50) = 3.1 mg/kg), although in sigm a binding assays the affinities were 3-and 30-fold less than caramiphe n, respectively. In the presence of 250 mu M of phenytoin, caramiphen and p-aminocaramiphen showed 3- to 5-fold increases in affinity for [H -3](+)pentazocine binding, whereas p-iodocaramiphen, which was inactiv e as an anticonvulsant, showed no change in affinity for sigma binding . These results indicate that anticonvulsant activity of the caramiphe n analogs is not due to interaction with sigma binding sites.