Interactions between 3,4-methylenedioxymethamphetamine and sigma1 receptors.

Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) are structurally similar and represent a serious and growing health threat. Earlier studies in our laboratory have shown that methamphetamine interacts with sigma receptors and that antagonism of these receptors can attenuate methamphetamine-induced locomotor stimulation and neurotoxicity. However, no research exists which characterizes the interaction between sigma receptors and MDMA. Therefore, the goal of the present study was to determine whether sigma receptors are involved in the actions of MDMA. In the first part of the study, competition and saturation binding assays were performed to measure the interaction of MDMA with sigma receptors. The receptor binding assays revealed that MDMA interacts preferentially with the sigma(1) subtype, as compared to the sigma(2) subtype, and that this interaction occurs in a competitive manner. The second part of the study focused on behavioral measurements in male, Swiss Webster mice to determine whether a selective sigma(1) receptor antagonist, BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine, 0-30 mg/kg, i.p.) could attenuate the locomotor stimulant actions of MDMA (0-50 mg/kg, i.p.). BD1063 alone had no effect on locomotor activity, but dose-dependently attenuated the locomotor stimulant effects of MDMA and produced a significant shift to the right in the MDMA dose response curve. Together, the data support the functional relevance of the interaction of MDMA with sigma(1) receptors, and suggest that these receptors are involved in the stimulant actions of MDMA.

Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice.

Previous studies have shown that BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and related analogs attenuate the toxicity and stimulant effects of cocaine through antagonism of sigma receptors. In the present study, six analogs of BD1008 (UMB 98-103) were synthesized and evaluated in receptor binding and behavioral studies. Competition binding studies confirmed that all six compounds have high affinity for sigma1 receptors, moderate affinity for sigma2 receptors, and low to negligible affinity for monoamine transporters, opioid, N-methyl-D-aspartate, dopamine, and 5-HT receptors. In behavioral pharmacological studies, pretreatment of mice with UMB 100, UMB 101, or UMB 103 significantly attenuated cocaine-induced convulsions and lethality. Together with earlier studies, the data suggest that analogs of BD1008 are promising medication development leads for reducing the toxicity of cocaine.

Review of the pharmacological and clinical profile of rimcazole.

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.