Sigma-1 Research Articles

Ayahuasca and its interaction with the sigma-1 receptor: a potential treatment for COVID-19

Ayahuasca and its interaction with the sigma-1 receptor: a potential treatment for COVID-19

Ayahuasca and its interaction with the sigma-1 receptor: a potential treatment for COVID-19.

Ayahuasca and its interaction with the sigma-1 receptor: a potential treatment for COVID-19.

Auvelity as a Potential Treatment for Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia affecting older adults. Alzheimer’s disease also shares a significant association with Major Depressive Disorder. Glutamatergic excitotoxicity via NMDA receptors is believed to be a key mechanism underlying neurodegeneration in Alzheimer’s Disease. Blockade of NMDA receptors by NMDA antagonists like Memantine appears to inhibit glutamatergic excitotoxicity. Memantine also increases dopaminergic activation through agonism of sigma-1 receptors. The combination of these two mechanisms is believed to underlie Memantine’s improvements in memory, cognition and general functioning in AD patients. Auvelity was recently approved by the FDA for the treatment of Major Depressive Disorder in adults. Auvelity’s relevant mechanism of action is a combination of its blockade of NMDA receptors with consequent antagonism of the glutamatergic neurotransmitter pathway, and its agonism of the sigma-1 receptor. Because Auvelity and AD medications like Memantine employ the same mechanism of action, it is hypothesized that Auvelity might be a potential medical treatment for reducing the symptoms of Alzheimer’s disease.

Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ1 receptor antagonist BD-1063. The selective σ1 receptor agonist PRE-084 completely reversed this effect. Four thioamide H2S-σ1 receptor hybrids (5a−8a) and their amide derivatives (5b−8b) were synthesized. Compound 7a (AD164) robustly released H2S and showed selectivity for σ1 receptor over σ2 and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous H2S-release and σ1 antagonistic activities.

The effect of ALS-related mutation on lipid binding of sigma-1 receptor and its relationship with agonist action

The effect of ALS-related mutation on lipid binding of sigma-1 receptor and its relationship with agonist action

Sigma Receptors Ligands: New insights into the Cardioprotective Potential

Cardiovascular diseases (CVDs) are primary reason of mortality and morbidity worldwide. Angina pectoris (AP), myocardial infarction (MI), silent myocardial ischemia and sudden cardiac death occur due to blockage in the coronary artery by atherosclerotic clot. Atherosclerotic clot is a systemic inflammatory process characterised by the accumulation and subsequent thickening of the wall by blood borne materials like low-density lipoproteins and macrophages/lymphocytes within the intima of arteries. These initial fatty streak lesions may also evolve into vulnerable plaques susceptible to rupture or erosion. Plaque rupture initiates both platelet adhesion and aggregation as well as the activation of the clotting cascade leading to so-called athero-thrombotic process and leads to coronary artery blockade. Coronary artery blockage interrupts the coronary blood supply leading to damage of myocardium. Multiple factors such as intra cellular (Ca2+, pH) and inter cellular (adhesion molecules) factors, inflammation, environmental toxins as well as metals and oxygen free radicals are involved in the pathogenesis of coronary artery diseases. Furthermore, certain sigma receptor ligands have been reported to show protective action against coronary artery diseases. Sigma receptor, a transmembrane protein, is expressed in many tissues including cardiovascular, liver and central nervous system. Sigma ligands significantly prevented the deviated biochemical parameters such as cardiac marker enzymes, lipid profile and antioxidant parameters to near normal status. Therefore, sigma receptor stimulation represents a new therapeutic strategy to prevent heart from ischemic and hypertrophic dysfunction in case of cardiovascular disorders. This review summarises the sigma receptors and cardioprotective potential of sigma receptor ligands. The article also provides a comprehensive account of structure, types and medical efficacy of cardioprotective sigma agonists.

Computer-Aided Drug Discovery (CADD) Approaches for the Management of Neuropathic Pain.

Neuropathic pain occurs due to physical damage, injury, or dysfunction of neuronal fibers. The pathophysiology of neuropathic pain is too complex. Therefore, an accurate and reliable prediction of the appropriate hits/ligands for the treatment of neuropathic pain is a challenging process. However, computer-aided drug discovery approaches contributed significantly to discovering newer hits/ligands for the treatment of neuropathic pain. The computational approaches like homology modeling, induced-fit molecular docking, structure-activity relationships, metadynamics, and virtual screening were cited in the literature for the identification of potential hit molecules against neuropathic pain. These hit molecules act as inducible nitric oxide synthase inhibitors, FLAT antagonists, TRPA1 modulators, voltage-gated sodium channel binder, cannabinoid receptor-2 agonists, sigma-1 receptor antagonists, etc. Sigma-1 receptor is a distinct type of opioid receptor and several patents were obtained for sigma-1 receptor antagonists for the treatment of neuropathic pain. These molecules were found to have a profound role in the management of neuropathic pain. The present review describes the validated therapeutic targets, potential chemical scaffolds, and crucial protein-ligand interactions for the management of neuropathic pain based on the recently reported computational methodologies of the present and past decades. The study can help the researcher to discover newer drugs/drug-like molecules against neuropathic pain.

Inhibition of SARS-CoV-2 infection in human iPSC-derived cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoarchitecture and beating.

SARS-CoV-2 infects cardiac cells and causes heart dysfunction. Conditions such as myocarditis and arrhythmia have been reported in COVID-19 patients. The Sigma-1 receptor (S1R) is a ubiquitously expressed chaperone that plays a central role in cardiomyocyte function. S1R has been proposed as a therapeutic target because it may affect SARS-CoV-2 replication; however, the impact of the inhibition of S1R in human cardiomyocytes remains to be described. In this study, we investigated the consequences of S1R inhibition in iPSC-derived human cardiomyocytes (hiPSC-CM). SARS-CoV-2 infection in hiPSC-CM was productive and reduced cell survival. S1R inhibition decreased both the number of infected cells and viral particles after 48 hours. S1R inhibition also prevented the release of pro-inflammatory cytokines and cell death. Although the S1R antagonist NE-100 triggered those protective effects, it compromised cytoskeleton integrity by downregulating the expression of structural-related genes and reducing beating frequency. Our findings suggest that the detrimental effects of S1R inhibition in human cardiomyocytes’ integrity may abrogate its therapeutic potential against COVID and should be carefully considered.

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties.

In an attempt to extend recent studies showing that some clinically evaluated histamine H3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (σ1R), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ1R than σ2R with the highest binding preference to σ1R for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H3/σ1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH3R Ki = 3.17 and 7.70 nM, σ1R Ki = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein–ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H3 and σ1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ1 or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.

Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1G93A mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1G93A mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1G93A mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.

Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect

The sigma-1 (σ1) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest-affinity was displayed at the σ1, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ1 receptor agonism, in two memory tests. Automated receptor–small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ1 receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.

Dependence of glucose transport on autophagy and GAPDH activity

Glucose uptake in the brain is critically important to brain health. Using two widely used cell line model systems, we have found that siramesine, a lysosomotropic agent and ligand for the sigma-2 receptor, inhibits glucose uptake and decreases pools of the GLUT1 glucose transporter at the plasma membrane. Siramesine induces autophagy but also disrupts degradation of autophagy substrates, providing a potential mechanism for its action on glucose uptake. In other cell systems, many of the effects of siramesine can be suppressed by α -tocopherol, a type of vitamin E and potent antioxidant, and α-tocopherol also suppressed the effect of siramesine on glucose uptake, suggesting a role for reactive oxygen species and membrane maintenance. We have also identified a novel mechanism for siramesine in which it inhibited plasma membrane levels of GAPDH, a key protein in glycolysis which localizes to the plasma membrane in some cell types. Indeed, GAPDH inhibitors decreased glucose uptake, like siramesine, likely through an overlapping pathway with siramesine. GAPDH inhibitors induced autophagy but inhibited degradation of autophagy targets. Thus, we have identified novel mechanisms required for glucose uptake which may have important implications in disease.

Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects.

Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.

Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors

A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K i = 0.44 nmol/L; sigma-1: K i = 0.27 nmol/L), and good metabolic stability (T 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.

Fluvoxamine for the Early Treatment of SARS-CoV-2 Infection: A Review of Current Evidence.

SARS-CoV-2 infection causes COVID-19, which frequently leads to clinical deterioration and/or long-lasting morbidity. Academic and governmental experts throughout the USA met in 2021 to discuss the potential for use of fluvoxamine as early treatment of SARS-CoV-2 infection. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is a strong sigma-1 receptor agonist, and this may effectively reduce cytokine production, preventing clinical deterioration. This repurposed psychiatric medication has a well-known safety record, is inexpensive, easy to use, and widely available, all of which are advantages during this global COVID-19 pandemic. At the meeting, experts reviewed the existing published literature on the use of fluvoxamine as experimental COVID-19 treatment, as well as prior research on the potential mechanisms for anti-inflammatory effects of fluvoxamine, including for other conditions including sepsis. Investigators shared current trials underway and existing gaps in knowledge. Two randomized controlled trials and one observational study examining the effect of fluvoxamine in COVID-19 treatment have found high efficacy. Four larger randomized clinical trials are currently underway, including three in the USA and Canada. More data are needed on dosing and mechanisms of effect; however, fluvoxamine appears to have substantial potential as a safe and widely available medication that could be repurposed to ameliorate serious COVID-19-related morbidity and mortality. As of April 2021, fluvoxamine was mentioned in the NIH COVID-19 treatment guidelines, although no recommendation is made for or against use. Available data may warrant clinician discussion of fluvoxamine as a treatment option for COVID-19, using shared decision making. Video Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01636-5.

P.0052 Sigma1 receptor antagonists and the ability to block a compulsive-like eating episode in a preclinical model of binge eating

P.0052 Sigma1 receptor antagonists and the ability to block a compulsive-like eating episode in a preclinical model of binge eating

Safety and efficacy of fluvoxamine in COVID-19 ICU patients: An open label, prospective cohort trial with matched controls.

AimsFluvoxamine, a selective serotonin reuptake inhibitor (SSRI) and sigma‐1 receptor agonist, has so far shown promise in the prevention of COVID‐19 progression as an early treatment option in three trials. The aim of this study was to evaluate the safety and efficacy of fluvoxamine in COVID‐19 patients if administered later in the course of the disease.MethodsThe study was designed as an open‐label, prospective cohort trial with matched controls. In April and May 2021, 51 ICU COVID‐19 patients hospitalised in the University Hospital Dubrava and University Hospital Centre Zagreb, Croatia, were treated with fluvoxamine 100 mg three times daily for 15 days in addition to standard therapy and they were prospectively matched for age, gender, vaccination against COVID‐19, disease severity and comorbidities with 51 ICU controls.ResultsNo statistically significant differences between groups were observed regarding the number of days on ventilator support, duration of ICU or total hospital stay. However, overall mortality was lower in the fluvoxamine group, 58.8% (n = 30/51), than in the control group, 76.5% (n = 39/51), HR 0.58, 95% CI (0.36–0.94, P = .027).ConclusionFluvoxamine treatment in addition to the standard therapy in hospitalised ICU COVID‐19 patients could have a positive impact on patient survival. Further studies on the effects of fluvoxamine in COVID‐19 patients are urgently required.

The protective role of dimethyltryptamine and its analogues against ischemiareperfusion injury: Commentary

The article entitled “N,N-Dimethyltryptamine [DMT] attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain” by Szabo et al. published recently in Neuropharmacology [1] is the last one in the series of studies on the potential benefits of DMT administration in different clinical forms of ischemia-reperfusion injury (IRI).

Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers.

This long-term research was designed to evaluate whether superoxide dismutase (SOD) isoenzymes participate in the development of human gastrointestinal neoplasms and the potential influence of the sigma1 receptor (Sig1R) on the regulation of SOD gene expression during the neoplastic process. The experiments included human tissues from selected gastrointestinal tract tumors (liver cancer, colorectal adenocarcinoma, and colorectal cancer liver metastases). Activity, protein levels, and mRNA levels were determined for SOD isoenzymes and Sig1R. Additionally, markers of oxidative stress (glutathione, lipid peroxidation) were measured. The results showed significant changes in the antioxidant system activity in all examined types of tumors. SOD changed both in healthy cells and in neoplastic cells. The activity and expression of all studied enzymes significantly changed due to the advancement of tumor development. The Sig1R might be an additional regulator of the antioxidant system on which activity might depend on the survival and proliferation of cancer cells. Overall, the study shows that SOD1 and SOD2 are involved not only in the formation of neoplastic changes in the human gastrointestinal tissues (healthy intestine – colon tumor; healthy liver – liver cirrhosis – liver cancer) but also in the development of tumors in the sequence: benign tumor – malignant tumor – metastasis.

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells.

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.