Evidence that the potential antipsychotic agent rimcazole (BW 234U) is a specific, competitive antagonist of sigma sites in brain

Abstract Rimcazole (BW 234U) is a potential antipsychotic agent which in open-clinical trials appears to be effective in acute schizophrenic patients. In the present study, rimcazole was found to block the specific binding of [ 3 H]−(+)−SKF 10,047 to sigma sites in rat and guinea pig brain (IC 50 = 5.0 x 10 −7 M). The compound was 100 times weaker as a blocker of phencyclidine sites (IC 50 = 4.3 x 10 −5 M). At 1 x 10 −5 M, rimcazole had only weak effects on μ, δ, κ and ϵ opioid receptors. Scatchard analysis of the binding data from guinea pig brain revealed an apparent K D for [ 3 H]−(+)− SKF 10, 047 of 85 ± 5 nM and a B max of 824 ± 27 fmole/mg protein. In the presence of 5 x 10 −7 M BW 234U, the apparent K D was 165 ± 35 nM, but the B max (892 ± 146 fmoles/mg protein) was not affected. This suggests that rimcazole is a competitive inhibitor of sigma sites. The agent was also capable of blocking sigma sites in vivo (ID 50 = 6 mg/kg i.p., mice) as judged by an in vivo sigma receptor binding assay. Thus, if the antipsychotic activity of rimcazole is confirmed in double-blind, placebo-controlled trials, it would be the first compound whose mechanism of antipsychotic activity may best be explained by a direct blockade of sigma sites and not by a direct blockade of dopamine (D 2 ) receptors in brain.