BW234U,(<i>cis</i>-9-[3–(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride): a novel antipsychotic agent

Ferris, Robert M.; Harfenist, M.; McKenzie, Gerald M.; Cooper, Barrett R.; Soroko, Francis E.; Maxwell, Robert A.

doi:10.1111/j.2042-7158.1982.tb04736.x

Cited by 53 publications

(24 citation statements)

References 7 publications

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“…This rat glioma cell line has been used extensively in previous research because it expresses high densities of both s-1 and s-2 receptors (6). Rimcazole (s-1/s-2 receptor antagonist), haloperidol (s-1/s-2 receptor antagonist), (1)-pentazocine (s-1 receptor agonist), and AC915 (s-1 receptor antagonist) were chosen as our model compounds because these drugs are commercially available and are potent s-receptor ligands (20)(21)(22)(23). Several metabolic PET tracers, such as 18 F-FDG, 39-deoxy-39-fluorothymidine ( 18 F-FLT), 11 C-choline, and 11 C-methionine, are routinely produced in our laboratory.…”

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confidence: 99%

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Rybczynska¹,

Dierckx²,

Ishiwata³

et al. 2008

J Nucl Med

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Tumor cells can be selectively killed by application of s-ligands; high concentrations (20-100 mM) are often required, however, because either diffusion barriers must be passed to reach intracellular sites or the entire s-receptor population should be occupied to induce cell death. We measured receptor occupancies associated with the cytotoxic effect and dose-dependent changes of cellular metabolism in a tumor cell line. Methods: C6 cells (rat glioma) were grown in monolayers and exposed to (1)-pentazocine (s-1 agonist), AC915 (s-1 antagonist), rimcazole (s-1/s-2 antagonist), or haloperidol (s-1/s-2 antagonist). Occupancy of s-receptors by the test drugs was measured by studying the competition of the test drugs with cellular binding of the ligand 11 C-SA4503. Metabolic changes were quantified by measuring cellular uptake of 18 F-FDG, 18 F-FLT, 11 C-choline, or 11 Cmethionine. Cytotoxicity was assessed by cellular morphology observation and cell counting after 24 h. Results: IC 50 values (drug concentrations resulting in 50% occupancy of the available binding sites) of the test drugs for inhibition of cellular 11 C-SA4503 binding were 6.5, 7.4, 0.36, and 0.27 mM for (1)-pentazocine, AC915, rimcazole, and haloperidol, respectively. EC 50 values (dose required for a 50% reduction of cell number after 24 h) were 710, 819, 31, and 58 mM, for pentazocine, AC915, rimcazole, and haloperidol, respectively. Cytotoxic doses of s-ligands were generally associated with increased uptake of 18 F-FDG, decreased uptake of 18 F-FLT and 11 C-choline, and little change in 11 C-methionine uptake per viable cell. Conclusion: IC 50 values of the test drugs reflect their in vitro affinities to s-2 rather than to s-1 receptors. Because cytotoxicity occurred at concentrations 2 orders of magnitude higher than IC 50 values for inhibition of cellular 11 C-SA4503 binding, high (99%) occupancy of s-2 receptors is associated with loss of cell viability. 18 F-FLT, 11 C-choline, and 18 F-FDG responded most strongly to drug treatment and showed changes corresponding to the cytotoxicity of the test compounds.

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confidence: 99%

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Rybczynska¹,

Dierckx²,

Ishiwata³

et al. 2008

J Nucl Med

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“…In the original clinical trials, rimcazole caused convulsions when given at high doses (19,28,38), and a similar effect has also been reported in animals (21). Several lines of evidence suggest that the role of ó receptors in convulsions might be to regulate the activity of glutamatergic systems via the modulation of NMDA receptors (97,98,119).…”

Section: Convulsive Effectsmentioning

confidence: 71%

Review of the Pharmacological and Clinical Profile of Rimcazole

2004

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Rimcazole is a carbazole derivative that acts in part as a sigma receptor antagonist. Wellcome Research Laboratories introduced this compound during the 1980s when it was hypothesized to be a novel antipsychotic with an improved side effect profile. However, subsequent clinical trials demonstrated that rimcazole lacked efficacy in schizophrenic patients and it is now primarily used as an experimental tool. In addition to its actions as a sigma receptor antagonist, rimcazole also has high affinity for dopamine transporters, and in recent years it has served as a lead compound for the development of novel dopamine transporter ligands. Although rimcazole cannot be considered a selective ligand for sigma receptors, the recent development of other selective agonists and antagonists for sigma receptors have aided in clarifying the involvement of these receptors in the actions of rimcazole. Many of the physiological and behavioral effects of rimcazole can in fact be ascribed to its action as a sigma receptor antagonist, although there are exceptions. Rimcazole is likely to have a continued role in elucidating sigma receptor function in either in vitro or in vivo systems where sigma receptor-mediated effects can be studied independently of the influence of dopamine and serotonin transporters.

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“…Kanzaki et al (DA) is plentiful (Graybiel etal., 1989;Largent etal., 1984;Tam etal., 1983). Sigma antagonists have attenuated apomorphine-induced behavior (Ferris et al, 1982;Taylor et al, 1985). Furthermore, electrophysiological studies have shown that sigma drugs modulate the activity of DA neurons in areas A9 and A10 (Ceci etal., 1988;Steinfels etal., 1989).…”

Section: Introductionmentioning

confidence: 98%

BMY-14802 reverses the reduction of striatal dopamine release induced by (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine

Kanzaki

Okumura

Ujike

et al. 1992

J. Neural Transmission

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Intraperitoneal injection of (+)-3-[3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), a sigma receptor agonist, significantly reduced the striatal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) measured by in vivo microdialysis. These reductions were significantly greater at (+)-3PPP doses of 12 and 24 mg/kg than at 1 mg/kg. The levels of 5-hydroxyindoleacetic acid (5HIAA) were increased by the injection of (+)-3PPP in dose of 24 mg/kg, but were not affected at lower doses. BMY-14802, a sigma antagonist, alone at doses of 15 mg/kg and 30 mg/kg did not affect the levels of DA, DOPAC, HVA and 5HIAA. Pretreatment with 30 mg/kg BMY-14802 reversed the reduction of the levels of DA induced by 12 mg/kg (+)-3PPP. Although neither 30 mg/kg BMY-14802 nor 12 mg/kg (+)-3PPP affected the levels of striatal 5HIAA, combined treatment with both produced a significant elevation. These findings clearly demonstrate that sigma receptors may regulate DA release from the striatal presynapse.

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BW234U,(cis-9-[3–(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride): a novel antipsychotic agent

Cited by 53 publications

References 7 publications

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Review of the Pharmacological and Clinical Profile of Rimcazole

BMY-14802 reverses the reduction of striatal dopamine release induced by (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine

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