Review of the Pharmacological and Clinical Profile of Rimcazole

Abstract

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.

Antagonists show GTP‐sensitive high‐affinity binding to the sigma‐1 receptor

“…Indeed, we were able to produce a dose-response curve in the absence of Fura-2-loaded cells with an apparent EC50 of approximately 10 mM (data not shown). However, rimcazole did not interfere with the reading of the MTS assay, and was found to inhibit metabolic activity of MDA-MB-468 cells with a pIC50 4.4 Ϯ 0.2 (n = 5; IC50 45 mM) which is over 30 times higher than the published affinity for the sigma-1 receptor (0.9 mM; Gilmore et al, 2004). The affinity of rimcazole was therefore assessed, and the effect of GTP on rimca- zole binding measured in Figure 6.…”

“…We also tested a second sigma-1 receptor antagonist, rimcazole, which has a published affinity for this receptor of 0.9 mM (Gilmore et al, 2004) and has been previously shown to cause apoptosis in cancer cells through a sigma-1 receptordependent pathway (Spruce et al, 2004). We were unable to use rimcazole in the calcium assay as it interfered with the wavelengths at which Fura-2 is read, fluorescing intensely at 510 nm.…”

“…The affinity of IPAG for the sigma-1 receptor also shifts to the low-affinity site (pKi 6.3 Ϯ 0.2, Ki 500 nM) in the presence of GTP, which has no significant difference from the low-affinity site seen in the two-site fit in the absence of GTP (pKi 6.8; t-test P-value 0.183). Competition assays performed using intact cells also showed low-affinity binding to a single site [pKi 5.1 Ϯ 0.2, n = 7 (Ki 8 mM)].We also tested a second sigma-1 receptor antagonist, rimcazole, which has a published affinity for this receptor of 0.9 mM (Gilmore et al, 2004) and has been previously shown to cause apoptosis in cancer cells through a sigma-1 receptordependent pathway (Spruce et al, 2004). We were unable to use rimcazole in the calcium assay as it interfered with the wavelengths at which Fura-2 is read, fluorescing intensely at 510 nm.…”

Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-β25–35

“…Afobazole was applied at 30 mM in the absence and presence of the selective s-1-and s-2-receptor antagonist BD-1047 (10 mM) (Matsumoto et al, 1995) and rimcazole (300 nM) (Gilmore et al, 2004), and migration in response to Ab 25-35 was assessed. Afobazole alone decreased microglial migration caused by Ab 25-35 by 29 6 1%.…”

HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

“…Although rimcazole itself is a non-selective s ligand that also binds the dopamine transporter (Gilmore et al, 2004), highly specific small molecule s-1 agonists do exist. In s-1 knockout mice, binding of brain membranes to the s-1 agonist ( þ )-pentazocine is abolished, providing evidence that ( þ )-pentazocine acts solely through s-1 sites (Langa et al, 2003).…”