Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic Perspectives

Zamanillo, Daniel; Portillo‐Salido, Enrique; Vela, José Miguel; Romero, Luz

doi:10.1002/9781118185537.ch6

Cited by 11 publications

(11 citation statements)

References 273 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Modulators of Sigma-1 Receptor: A Review

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

Allosteric Modulators of Sigma-1 Receptor: A Review

et al. 2019

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“…Maurice and Su, 2009; Zamanillo et al, 2012), as well as a number of previous reviews of the behavioral effects of various ligands for the σR (e.g. Leonard, 2004; Skuza and Wedzony, 2004).…”

Section: Introductionmentioning

confidence: 99%

A role for sigma receptors in stimulant self-administration and addiction

Katz

Hong²,

Hiranita³

et al. 2016

Behavioural Pharmacology

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Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other sub-cellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces reinforcing effects of σR agonists, due to dopamine transporter actions. Once established the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical in the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for reinforcing effects of abused drugs. However, the self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including reinforcing effects assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant, and once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

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“…Thus, the synthesis of such S1R ligands represents a promising strategy to develop novel treaments for various CNS diseases or even cancers [32][33]. Many drugs described in the literature show affinity for S1R, and some of them have undergone clinical trials, but no selective S1R ligands have so far been marketed [34]. A phase 2 study is ongoing to evaluate Anavex 2-73a mixed muscarinic and S1R agonist -in patients with Alzheimer's disease [35,36].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands

Donnier-Maréchal

Carato

Larchanché

et al. 2017

European Journal of Medicinal Chemistry

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A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC/Ki ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.

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Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic Perspectives

Cited by 11 publications

References 273 publications

Allosteric Modulators of Sigma-1 Receptor: A Review

Allosteric Modulators of Sigma-1 Receptor: A Review

A role for sigma receptors in stimulant self-administration and addiction

Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands

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