, Volume 18, Issue 5, pp 269-284
Date: 29 Aug 2012

σ-1 Receptor Ligands

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Abstract

The σ receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that σ receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of σ receptor exist, the σ-1 receptor and the σ-2 receptor. σ-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with σ-1 receptors. σ-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders.

Selective σ-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to σ-1 receptors. As a result of these findings, σ-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of σ-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. σ-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients.

A number of preclinical studies have shown that selective agonists of σ-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that σ-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the σ-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of σ-1 receptor ligands is their ‘modulatory’ role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed.

Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of σ-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that σ-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.