Anticonvulsant activity of caramiphen analogs

Abstract

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 σ recognition sites in brain. To study the structureactivity 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 σ binding affinity. Some of the analogs potently inhibited σ binding but were devoid of anticonvulsant activity. Aminocaramiphen 2 (ED 50 = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylcyclopentanecarboxylate 9 (ED 50 = 4.8 mg/kg) showed anticonvulsant activity comparable to caramiphen (ED 50 = 3.1 mg/kg), although in σ binding assays the affinities were 3-and 30-fold less than caramiphen, respectively. In the presence of 250 μM 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 σ binding. These results indicate that anticonvulsant activity of the caramiphen analogs is not due to interaction with o binding sites.