Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

Abstract

Many antidepressant drugs interact with σ receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. σ Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel σ receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for σ receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The σ receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that σ receptor agonists represent a possible new class of antidepressant medication.

σ-1 receptors in major depression and anxiety

“…Furthermore, the s-receptor agonist igmesine has also been found to be effective in the senescence-accelerated mouse, and it is therefore speculated to be useful in treating age-related mood disorders [73]. Similarly, administration of SA-4503 is known to ameliorate the behavioral deficits resembling depression symptoms in olfactory bulbectomized rats [72].…”

“…In another study, 1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/ CRA0450), an orally active corticotropin releasing factor-1 and s-1 receptor antagonist, has demonstrated antidepressant and anxiolytic activity in animal models [71]. UMB23 and UMB82, two novel s-receptor agonists, dose-dependently reduce the immobility time in the forced swim test, with this action reversed by BD 1047 [72]. Furthermore, the s-receptor agonist igmesine has also been found to be effective in the senescence-accelerated mouse, and it is therefore speculated to be useful in treating age-related mood disorders [73].…”

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

“…Of interest in this regard is the idea that antidepressants, including selective serotonin reuptake inhibitors (SSRI) like fluvoxamine, may be useful addon treatments for the negative symptoms of schizophrenia (for a review see Rummel et al, 2005;Moller, 2005). Incidentally, the relatively high affinity of fluvoxamine and selected other antidepressants has led some to suggest that sigma 1 receptors may play a role in the treatment of depression (Narita et al, 1996;Yagasaki et al, 2006;Wang et al, 2007;Dhir and Kulkarni, 2007) or obsessive-compulsive disorder (Egashira et al, 2007). The affinity we determined for the binding of fluvoxamine to the cloned human sigma 1 receptor is about five-fold higher than that reported in whole tissue (Narita et al, 1996).…”

“…The unparalleled ability of sigma 1 receptors to interact with a huge range of drug structural classes and its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders, including depression, psychosis, substance abuse, Alzheimer's disease, cerebral stroke, and other traumatic brain injuries (see Maurice et al, 1999;Su and Hayashi 2003;Hayashi and Su 2004;Nguyen et al, 2005;Yagasaki et al, 2006;Meunier et al, 2006;Wang et al, 2007;Martin-Fardon et al, 2007). This potential of sigma 1 receptors to serve as a pharmacotherapeutic target, or even as a side effect-mediating target, calls for a better understanding of the relationship between the sigma 1 receptor and its ligands.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…3,[235][236][237] To reiterate, multitarget approaches appear more promising than selective agents for manipulation of intracellular proteins-not least, because they can help vector drug actions to cerebral areas involved in the induction and control of depression. Nonetheless, if antidepressants are designed to act via intracellular mechanisms, then it must be established how to monitor their effects in humans.…”