Evidence that the potential antipsychotic agent rimcazole (BW 234U) is a specific, competitive antagonist of sigma sites in brain.
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 [3H]-(+)-SKF 10,047 to sigma sites in rat and guinea pig brain (IC50 = 5.0 X 10(-7) M). The compound was 100 times weaker as a blocker of phencyclidine sites (IC50 = 4.3 X 10(-5) M). At 1 X 10(-5) M, rimcazole had only weak effects on mu, delta, kappa and epsilon opioid receptors. Scatchard analysis of the binding data from guinea pig brain revealed an apparent KD for [3H]-(+)-SKF 10,047 of 85 +/- 5 nM and a Bmax of 824 +/- 27 fmole/mg protein. In the presence of 5 X 10(-7) M BW 234U, the apparent KD was 165 +/- 35 nM, but the Bmax (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 (ID50 = 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 (D2) receptors in brain.
Ferris
R M
RM
Tang
F L
FL
Chang
K J
KJ
Russell
A
A
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D003024:Clozapine / Q000378:metabolism; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma; D013469:Sulpiride / Q000378:metabolism
D014150:Antipsychotic Agents; D002227:Carbazoles; D011957:Receptors, Opioid; D017480:Receptors, sigma; D010643:Phenoxybenzamine; D008774:Methylphenidate; C012134:SK&F 10047; D013469:Sulpiride; D011433:Propranolol; C034931:rimcazole; D010620:Phenazocine; D010622:Phencyclidine; D003024:Clozapine; D001058:Apomorphine