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The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 44491

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Special Issue Editors

Dr. Carmen Abate

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Guest Editor

Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, Via Orabona 4, 70125 Bari, Italy
Interests: receptor; protein; drug design
Special Issues, Collections and Topics in MDPI journals

Dr. Tangui Maurice

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Co-Guest Editor

INSERM UMR-S1198, University of Montpellier, CEDEX 5, 34095 Montpellier, France
Interests: sigma-1 receptor; neuroprotection; neurodegenerative diseases; Alzheimer; butyrylcholinesterase; learning and memory; brain plasticity; animal behavior
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Almost five decades after their discovery, the role of sigma receptors in health and disease is still an intriguing subject. The sigma-1 subtype has been defined as a pluripotent chaperone that interacts with several client proteins. Its recently obtained crystal structure, which shows a peculiar folding, will facilitate the understanding of the oligomerization/polymerization processes that address the sigma-1 receptor functions. Drugs interacting with the sigma-1 subtype have potential for the treatment of CNS disfunctions, neurodegenerative diseases, pain, cocaine abuse, and tumors. After diverse hypotheses, the sigma-2 subtype was recently identified as TMEM97, rejuvenating the interest in sigma-2-related research. The overexpression of this subtype in tumor tissues and its role in cell proliferation have mostly driven the research in the oncology field, but recent evidence has highlighted the sigma-2 as the receptor responsible for the binding of Abeta oligomers to neurons; one sigma-2 ligand is now in clinical trials for the treatment of the Alzheimer’s disease. Surprisingly, sigma receptors have been identified as host proteins for the interaction with the SARS-CoV-2 proteins, with one sigma ligand performing 20-fold better than hydroxychloroquine in the antiviral assays.

The present thematic issue will collect data from the experts in the sigma receptor field with the aim of disseminating the knowledge about these pluripotent proteins and advancing the research toward their full understanding and possible therapeutic applications.

Dr. Carmen Abate
Guest Editor
Dr. Tangui Maurice
Co-Guest Editor

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Keywords

sigma-1 receptor
sigma-2 receptor
TMEM97
cancer
neurodegeneration
neuroprotection
pain
SAR
SAfiR
CNS disorders

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Published Papers (12 papers)

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18 pages, 38993 KiB

Open AccessArticle

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

by Gundega Stelfa, Edijs Vavers, Baiba Svalbe, Rinalds Serzants, Anna Miteniece, Lasma Lauberte, Solveiga Grinberga, Baiba Gukalova, Maija Dambrova and Liga Zvejniece

Int. J. Mol. Sci. 2021, 22(21), 11611; https://doi.org/10.3390/ijms222111611 - 27 Oct 2021

Cited by 5 | Viewed by 3507

Abstract

Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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19 pages, 3227 KiB

Open AccessArticle

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

by Lucie Crouzier, Morgane Denus, Elodie M. Richard, Amarande Tavernier, Camille Diez, Nicolas Cubedo, Tangui Maurice and Benjamin Delprat

Int. J. Mol. Sci. 2021, 22(20), 11049; https://doi.org/10.3390/ijms222011049 - 13 Oct 2021

Cited by 12 | Viewed by 3661

Abstract

The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca²⁺ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r^+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1r^WT. The locomotion of the s1r^+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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17 pages, 2729 KiB

Open AccessArticle

Sigma-1 Receptor Agonists Acting on Aquaporin-Mediated H₂O₂ Permeability: New Tools for Counteracting Oxidative Stress

by Giorgia Pellavio, Giacomo Rossino, Giulia Gastaldi, Daniela Rossi, Pasquale Linciano, Simona Collina and Umberto Laforenza

Int. J. Mol. Sci. 2021, 22(18), 9790; https://doi.org/10.3390/ijms22189790 - 10 Sep 2021

Cited by 12 | Viewed by 2432

Abstract

Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H₂O₂ permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H₂O₂ permeability. The finding that small molecules can act on both S1R and AQP-mediated H₂O₂ permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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17 pages, 6444 KiB

Open AccessArticle

Novel High Affinity Sigma-1 Receptor Ligands from Minimal Ensemble Docking-Based Virtual Screening

by Szabolcs Dvorácskó, László Lázár, Ferenc Fülöp, Márta Palkó, Zita Zalán, Botond Penke, Lívia Fülöp, Csaba Tömböly and Ferenc Bogár

Int. J. Mol. Sci. 2021, 22(15), 8112; https://doi.org/10.3390/ijms22158112 - 29 Jul 2021

Cited by 7 | Viewed by 3143

Abstract

Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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17 pages, 7157 KiB

Open AccessArticle

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

by Núria Gaja-Capdevila, Neus Hernández, Daniel Zamanillo, Jose Miguel Vela, Manuel Merlos, Xavier Navarro and Mireia Herrando-Grabulosa

Int. J. Mol. Sci. 2021, 22(13), 6956; https://doi.org/10.3390/ijms22136956 - 28 Jun 2021

Cited by 8 | Viewed by 2949

Abstract

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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42 pages, 5494 KiB

Open AccessArticle

Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

by Héctor Torres-Gómez, Constantin Daniliuc, Dirk Schepmann, Erik Laurini, Sabrina Pricl and Bernhard Wünsch

Int. J. Mol. Sci. 2021, 22(11), 5685; https://doi.org/10.3390/ijms22115685 - 26 May 2021

Viewed by 2867

Abstract

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ₁ receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the “left” five-membered ring and various amino groups on the “right” side; (2) benzylamino or analogous amino moieties on the “right” side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ₁ affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ₁ affinity (K_i = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the “left” hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ₁ affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ₁ affinity of 9a (K_i = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ₁ receptor, which result in energetic values correlating well with their different σ₁ affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ₁ receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ₁ receptor-binding pocket, which explains the higher σ₁ affinity of the unsubstituted azapropellane 9a. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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22 pages, 3124 KiB

Open AccessArticle

Involvement of Chaperone Sigma1R in the Anxiolytic Effect of Fabomotizole

by Mikhail V. Voronin, Yulia V. Vakhitova, Inna P. Tsypysheva, Dmitry O. Tsypyshev, Inna V. Rybina, Rustam D. Kurbanov, Elena V. Abramova and Sergei B. Seredenin

Int. J. Mol. Sci. 2021, 22(11), 5455; https://doi.org/10.3390/ijms22115455 - 21 May 2021

Cited by 6 | Viewed by 3056

Abstract

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site’s amino acids common for established Sigma1R ligands, with the ΔG_bind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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19 pages, 5279 KiB

Open AccessArticle

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant ¹⁸F-Labelled σ₂ Receptor Ligand

by Rareş-Petru Moldovan, Daniel Gündel, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Steffen Fischer, Magali Toussaint, Dirk Schepmann, Bernhard Wünsch, Peter Brust and Winnie Deuther-Conrad

Int. J. Mol. Sci. 2021, 22(11), 5447; https://doi.org/10.3390/ijms22115447 - 21 May 2021

Cited by 7 | Viewed by 2642

Abstract

The σ₂ receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ₂ receptors in cancer cells and tissue in combination with the antiproliferative potency of σ₂ receptor ligands motivates the research in the field of σ₂ receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with ¹⁸F and evaluation regarding detection of σ₂ receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [¹⁸F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ₂ receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ₂ receptor ligand [¹⁸F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ₂ receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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9 pages, 1854 KiB

Open AccessArticle

Choline-Sigma-1R as an Additional Mechanism for Potentiation of Orexin by Cocaine

by Jeffrey L. Barr, Pingwei Zhao, G. Cristina Brailoiu and Eugen Brailoiu

Int. J. Mol. Sci. 2021, 22(10), 5160; https://doi.org/10.3390/ijms22105160 - 13 May 2021

Cited by 4 | Viewed by 2217

Abstract

Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX₁ and OX₂, Gq-coupled GPCRs. We examined the effect of a selective OX₁ agonist, OXA (17-33) on cytosolic calcium concentration, [Ca²⁺]_i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca²⁺]_i in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX₁ receptors antagonist. In Ca²⁺-free saline, the OXA (17-33)-induced increase in [Ca²⁺]_i was not affected by pretreatment with bafilomycin A1, an endo-lysosomal calcium disrupter, but was blocked by 2-APB and xestospongin C, antagonists of inositol-1,4,5-trisphosphate (IP₃) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca²⁺]_i response elicited by OXA (17-33). Cocaine potentiated the increase in [Ca²⁺]_i by OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX₁ via choline-Sigma-1R and a critical role for Sigma-1R in the cocaine–orexin A interaction in nucleus accumbens neurons. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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16 pages, 939 KiB

Open AccessCommunication

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

by Vladimir Zhemkov, Michal Geva, Michael R. Hayden and Ilya Bezprozvanny

Int. J. Mol. Sci. 2021, 22(8), 4082; https://doi.org/10.3390/ijms22084082 - 15 Apr 2021

Cited by 30 | Viewed by 5575

Abstract

The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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Review

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27 pages, 15355 KiB

Open AccessReview

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

by Parthena Martin, Thadd Reeder, Jo Sourbron, Peter A. M. de Witte, Arnold R. Gammaitoni and Bradley S. Galer

Int. J. Mol. Sci. 2021, 22(16), 8416; https://doi.org/10.3390/ijms22168416 - 5 Aug 2021

Cited by 32 | Viewed by 5629

Abstract

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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32 pages, 17464 KiB

Open AccessReview

Multi-Target Directed Ligands (MTDLs) Binding the σ₁ Receptor as Promising Therapeutics: State of the Art and Perspectives

by Francesca Serena Abatematteo, Mauro Niso, Marialessandra Contino, Marcello Leopoldo and Carmen Abate

Int. J. Mol. Sci. 2021, 22(12), 6359; https://doi.org/10.3390/ijms22126359 - 14 Jun 2021

Cited by 17 | Viewed by 4278

Abstract

The sigma-1 (σ₁) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ₁ receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ₁ receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ₁ protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ₁ receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies. Full article

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles)

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