Abstract
Allosteric modulators of sigma-1 receptor (Sig1R) are described as compounds that can increase the activity of some Sig1R ligands that compete with (+)-pentazocine, one of the classic prototypical ligands that binds to the orthosteric Sig1R binding site. Sig1R is an endoplasmic reticulum membrane protein that, in addition to its promiscuous high-affinity ligand binding, has been shown to have chaperone activity. Different experimental approaches have been used to describe and validate the activity of allosteric modulators of Sig1R. Sig1R-modulatory activity was first found for phenytoin, an anticonvulsant drug that primarily acts by blocking the voltage-gated sodium channels. Accumulating evidence suggests that allosteric Sig1R modulators affect processes involved in the pathophysiology of depression, memory and cognition disorders as well as convulsions. This review will focus on the description of selective and non-selective allosteric modulators of Sig1R, including molecular structure properties and pharmacological activity both in vitro and in vivo, with the aim of providing the latest overview from compound discovery approaches to eventual clinical applications. In this review, the possible mechanisms of action will be discussed, and future challenges in the development of novel compounds will be addressed.
Highlights
The International Union of Basic and Clinical Pharmacology included sigma receptor in its list of receptors only in 2013 as a ligand-regulated non-opioid intracellular receptor (Alexander et al, 2013)
This review summarizes the literature and data on all known sigma-1 receptor (Sig1R) allosteric modulators, including discovery and development, in vitro and in vivo pharmacological activities and discussion on allosteric regulation of Sig1R
A detailed comparison of the effects of phenytoin on the binding of [3H](+)-pentazocine and [3H]NE100 using saturation and kinetics assays showed that phenytoin acts as PAM and can negatively modulate the binding of [3H]NE-100 by decreasing the specific binding and increasing the dissociation rate from Sig1R (Cobos et al, 2006), demonstrating significant allosteric effects on the Sig1R ligand binding to Sig1R
Summary
The International Union of Basic and Clinical Pharmacology included sigma receptor in its list of receptors only in 2013 as a ligand-regulated non-opioid intracellular receptor (Alexander et al, 2013). Allosteric modulators of Sig1R are described as compounds that can increase the activity of Sig1R ligands that compete with [3H](+)-pentazocine for binding to Sig1R. Several chemical derivatives of SKF83959 were synthesized to find a selective Sig1R allosteric modulator and to exclude the potential involvement of other receptors One of these newly synthesized compounds, called SOMCL-668 (Figure 2), did not exhibit affinity for human dopamine D1, D2, D3, serotonin 5-. A detailed comparison of the effects of phenytoin on the binding of [3H](+)-pentazocine and [3H]NE100 using saturation and kinetics assays showed that phenytoin acts as PAM and can negatively modulate the binding of [3H]NE-100 by decreasing the specific binding and increasing the dissociation rate from Sig1R (Cobos et al, 2006), demonstrating significant allosteric effects on the Sig1R ligand binding to Sig1R. Scopolamine-induced learning deficits; i.c.v. injection of amyloid Aß25−35 peptide; APPSwe mice (mice)
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