clozapine and rimcazole

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.

Topics: Animals; Antipsychotic Agents; Apomorphine; Binding, Competitive; Brain; Carbazoles; Clozapine; Guinea Pigs; Kinetics; Male; Methylphenidate; Mice; Phenazocine; Phencyclidine; Phenoxybenzamine; Propranolol; Receptors, Opioid; Receptors, sigma; Sulpiride

The accumulation of 3-methoxytyramine (3-MT), the O-methylated metabolite of dopamine (DA), in rat striatum was used to assess the effects of drugs on dopaminergic activity. This was accomplished by pretreating rats with pargyline to completely inhibit 3-MT catabolism. Under the conditions used, 3-MT accumulation was linear over time for at least 90 minutes. Apomorphine and gamma-butyrolactone, drugs which depress the activity of DA-containing neurons, decreased striatal 3-MT accumulation; whereas typical neuroleptics (haloperidol, fluphenazine, chlorpromazine), which increase the activity of DA-containing neurons, increased striatal 3-MT accumulation. In addition, a number of other drugs which block DA receptors and exert various atypical actions on dopaminergic functioning were examined. These "atypical" compounds (clozapine, buspirone, molindone) also increased striatal 3-MT accumulation, but were generally less potent than the typical neuroleptics examined. Moreover, the potencies of the typical neuroleptics and "atypical" compounds that were tested appear to be somewhat related to their affinities for D-2 DA receptors, as measured by their abilities to displace 3H-spiperone from rat striatal membrane preparations. Interestingly, this relationship was less evident when NaCl was omitted from the 3H-spiperone binding assay buffer. The potential antipsychotic drugs, BW 234U and SCH 23390, were also investigated for their effects on 3-MT accumulation and 3H-spiperone binding, and they were relatively inactive in both of these measures of dopaminergic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Butyrolactone; Animals; Antipsychotic Agents; Apomorphine; Benzazepines; Buspirone; Carbazoles; Chlorpromazine; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Fluphenazine; Haloperidol; Male; Molindone; Pargyline; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Regression Analysis