Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands

Abstract

Sigma (σ) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of σ receptors, termed σ1 and σ2. Of these two subtypes, the σ1 receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for σ1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates σ1 receptors. Certain neurosteroids are known to interact with σ1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, σ1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of σ1 receptors, focussing on σ1 ligand neuropharmacology and the role of σ1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of σ1 ligands.

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

“…This indicates a competitive interaction between PRE-084 and both sigma-1 antagonists. These results agree with the pharmacological profile of these drugs, as it is known that PRE-084, BD-1063, and S1RA bind to sigma-1 receptors (17,20).…”

“…We tested the effects of the sigma-1 antagonists BD-1063 and S1RA (17,20) and the sigma-1 agonist PRE-084 (20). The opioid antagonists used were the centrally penetrant naloxone hydrochloride and its peripherally restricted analog naloxone methiodide (18).…”

The cholinergic system, sigma-1 receptors and cognition

“…Antagonists do not affect Ca 2+ release when given alone, but they impede the potentiation of Ca 2+ efflux by sigma-1 receptor agonists. After [13,40]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)…”

Neuropharmacologic Studies on the Brain Serotonin_1A Receptor Using the Selective Agonist Osemozotan

“…σ 1 Receptors have a neuromodulatory role on the neurotransmitter system, including the serotonergic, noradrenergic, dopaminergic, glutamatergic, and cholinergic systems, and are related to depression. [145][146][147][148][149][150][151] Previous studies using in vivo microdialysis showed that fluvoxamine causes a transient increase in the extracellular levels of DA and/or NA in the prefrontal cortex, 137,152,153) but it is not known whether σ 1 receptors are involved in the neurochemical effect of fluvoxamine.…”