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Allosteric Modulators of Sigma-1 Receptor: A Review

Edijs Vavers1*, Liga Zvejniece1, Tangui Maurice2 and Maija Dambrova1
1Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
2MMDN, University of Montpellier, INSERM, EPHE, UMR-S1198, Montpellier, France
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.

Introduction
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). Two pharmacologically distinct subtypes of sigma receptor, namely, sigma-1 receptor (Sig1R) and sigma-2 receptor (Sig2R), have been identified (Hellewell and Bowen, 1990; Quirion et al., 1992; Hellewell et al., 1994). Sig2R is known also as endoplasmic reticulum-resident transmembrane protein TMEM97 (Alon et al., 2017) involved in the regulation of cholesterol homeostasis and cell differentiation (Bartz et al., 2009; Haller et al., 2012). Number of selective Sig1R and Sig2R ligands have been described confirming significant differences in the pharmacological regulation of these subtypes. Thus, far no allosteric modulators of Sig2R have been reported.

Sig1R is an integral membrane-bound protein that is found in the nuclear membrane and endoplasmic reticulum and mitochondria-associated membrane (Mori et al., 2013; Mavlyutov et al., 2015; Su et al., 2016). Sig1R is expressed in both the CNS and peripheral tissues (Su and Junien, 1994). Sig1R is widely distributed in the brain, and it concentrates in specific areas involved in memory, emotion and sensory and motor functions (Alonso et al., 2000; Cobos et al., 2008). Sig1R, as described by its functional nature, is a chaperone protein and a unique cell protein modulator [reviewed in (Su et al., 2016)] that can amplify or reduce the signaling initiated when interacting with target proteins (Hayashi and Su, 2007; Zamanillo et al., 2012; Rodríguez-Muñoz et al., 2015). Therefore, Sig1R demonstrates properties that can be attributed to both chaperone proteins and receptors. However, the notion that allosteric modulators of Sig1R are identified is an additional argument for the “receptor” view of Sig1R.

Allosteric regulation is the regulation of protein activity by binding an effector molecule at a site other than the orthosteric or active site of a protein (Figure 1). The binding of allosteric modulators to a target protein induces a conformational change in the protein structure and changes the activity of orthosteric ligands (Figure 1). Allosteric modulators can be positive or negative effectors (PAMs or NAMs, respectively). PAMs increase the activity of the ligand, while NAMs block it (Figure 1). To date phenytoin, some benzazepine derivatives and stereoisomers of methylphenylpiracetam have been reported as PAMs of Sig1R while NAMs of Sig1R have not yet been described. The definition of allosteric Sig1R modulators might be artificial due to a lack of information on the orthosteric binding site for Sig1R. It is thought that the orthosteric binding site for Sig1R ligands is the binding site of (+)-SKF-10,047 and (+)-pentazocine, benzomorphan compounds that were the first identified to bind to Sig1R with high affinity and selectivity (Martin et al., 1976; Su, 1982). Thus, 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.

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Allosteric Modulation of Sig1R
There are no clearly defined molecular mechanisms that could fully describe the function of Sig1R and the activity of Sig1R ligands. Thus, it is more difficult to describe the activity of allosteric modulators, which do not compete with orthosteric Sig1R ligands for binding in the active site of Sig1R but rather enhance the activity of Sig1R agonists. The crystal structure of Sig1R shows that the ligand-binding domain in the protein is highly conserved, and how ligands enter and exit this site remains unclear (Schmidt et al., 2016). The binding site for allosteric Sig1R modulators is probably located outside the orthosteric ligand-binding domain. Since allosteric modulators are compounds that induce a conformational change within the protein structure, PAMs should reorganize the Sig1R protein in a way that would allow agonists to freely enter the ligand-binding site. It has been discussed previously that phenytoin might induce a conformational change in the Sig1R and thus enhance the affinity of the orthosteric ligand [3H](+)-pentazocine for its binding site on Sig1R (Cobos et al., 2006), which fits classic description of the activity of allosteric modulators (Figure 6). However, it is not clear how allosteric modulators of Sig1R can distinguish between agonists and antagonists and then selectively enhance the activity of agonists, even though the agonists and antagonists sometimes contain the same structural moieties.

Classical models for allosteric modulation might not be attributed to allosteric modulation of Sig1R. Several previous experiments support the conclusion that in ligand binding, Sig1R functions as an oligomer (Schuster et al., 1995; Chu et al., 2013; Gromek et al., 2014). Therefore, oligomerization is a key functional property of the Sig1R that may be linked to ligand efficacy [Schmidt et al., 2016; reviewed in Chu and Ruoho (2016)] and could explain how ligands can regulate the activity of Sig1R (Figure 6). Sig1R ligands may regulate the activity of the receptor interaction with client proteins by altering the oligomeric/monomeric receptor ratio and favoring the oligomeric states (Mishra et al., 2015). It has been shown that the Sig1R agonist (+)-pentazocine increased the relative ratio of dimers and monomers, while the inhibitor haloperidol increased the incidence of higher oligomeric forms (Chu and Ruoho, 2016). This observation indicates that higher oligomeric forms of Sig1R might be functionally inactive (Figure 5A). Since all Sig1R allosteric modulators known thus far are PAMs and enhance the activity of Sig1R agonists, they might modulate Sig1R by stabilizing the agonist state of the receptor, providing an increase in the dimeric (Figure 5B) and/or monomeric (Figure 5C) protein forms.




Sig1R has already been described as a chaperone that modulates other receptor systems through heteromeric protein-protein interactions (Navarro et al., 2013; Pabba, 2013; Moreno et al., 2014; Su et al., 2016). Therefore, it is possible that heteromeric complexes formed by Sig1R and its target proteins could be regulated by allosteric modulators of Sig1R (Figure 6). Allosteric Sig1R modulators could serve as a bridge between Sig1R and its target proteins. The “molecular glue” concept was first discovered by observing the mechanism of action of natural products that promote immunomodulatory ternary complex formation (Che et al., 2018), and recently, some compounds of synthetic origin have been reported to induce novel protein-protein interactions [reviewed in (Che et al., 2018)]. The “molecular glue” principle could be attributed not only to heteromeric protein-protein interactions but also to homomeric Sig1R interactions and could explain how allosteric modulators could increase the number of Sig1R in the agonist state conformation, thus increasing the activity of Sig1R agonists.

Full article
https://www.frontiersin.org/articles/10.3389/fphar.2019.00223/full