Pharmacology and therapeutic potential of sigma(1) receptor ligands

Abstract

Sigma (sigma) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of sigma receptors, termed sigma(1) and sigma(2). Of these two subtypes, the sigma(1) 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 sigma(1) 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 sigma(1) receptors. Certain neurosteroids are known to interact with sigma(1) 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 Ca(2+) signaling. Sigma(1) 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, sigma(1) 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 sigma(1) receptors, focussing on sigma(1) ligand neuropharmacology and the role of sigma(1) receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of sigma(1) ligands.

Keywords: Sigma-1 receptors; analgesia; cocaine.; depression and anxiety; drugs of abuse; learning and memory; pain; schizophrenia.

Fig (1)

Putative model for σ₁ receptors proposed by Pal and coworkers [159]. Open cylinders represent the two putative transmembrane domains. Closed cylinders represent the steroid binding domain-like sites and the open hexagon represents a putative σ₁ ligand. A, Possible spatial arrangement of the ligand binding site involving both steroid binding domain-like sites. B, Alternative model for ligand interaction with the σ₁ receptor.

Fig (2)

Model of modulation by σ₁ receptors of InsP3-mediated calcium efflux, proposed by Hayashi and Su [60, 63]. InsP₃ receptors, ANK220 and σ₁ receptor form a complex in lipid droplets on the endoplasmic reticulum, which contain moderate amounts of free cholesterol and neutral lipids. In the presence of a σ₁ agonist, the σ₁ receptor-ANK220 complex is dissociated from InsP₃ receptors and translocated. As a result InsP₃ binding to its receptor increases and Ca2⁺ efflux is enhanced. In the presence of a σ₁ antagonist, ANK220 remains coupled to InsP₃ receptor, but σ₁ receptor is dissociated from the complex, impeding the potentiation of calcium efflux by σ₁ agonists.