Search Results (40)

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic efficacy in preclinical models, their in vivo efficacy and safety profiles require further clarification. Methods: Analogs of well-known selective S1R ligand UVM147 were synthesized using 3-component Ugi reactions and examined in vitro for receptor affinity in radioligand competition binding assays and in vivo with mouse models of neuropathic and inflammatory pain and adverse effects. Results: Three novel heterocyclic compounds (RO-4-3, RO-5-3, and RO-7-3) displayed in vitro nanomolar affinity with varying selectivity for both SR subtypes (S1R and S2R). When screened in vivo at a dose of 30 mg/kg s.c. in mice first subjected to chronic constriction injury (CCI), RO-5-3 and RO-7-3 possessed anti-allodynic potential, while UVM147 was inactive. Upon full characterization, RO-5-3 significantly attenuated mechanical allodynia in a dose-dependent manner, while RO-7-3 was ineffective at higher doses. Both compounds dose-dependently attenuated nociceptive behaviors in the mouse formalin assay. RO-5-3 induced mild respiratory depression without impairing locomotor activity, whereas RO-7-3 caused transient respiratory depression and locomotor impairment. Additionally, RO-5-3, but not RO-7-3, induced conditioned place aversion consistent with potential S2R involvement. Conclusions: RO-5-3 exerts antinociceptive and anti-allodynic effects with minimal adverse behavioral effects, supporting the role of SRs in pain modulation. These results add to growing evidence supporting the development of SR ligands as efficacious therapeutics for neuropathic pain with fewer clinical liabilities. Full article

Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to its role in neuroprotection and neuroinflammation. Building upon our previously identified S1R ligand (compound 1), we designed and synthesized six novel benzamide derivatives through pharmacomodulation to optimize affinity, selectivity, and safety profiles. Among these, compound 2 demonstrated superior S1R affinity, improved selectivity over the sigma-2 receptor (S2R), and favorable ADME properties, including enhanced permeability and markedly reduced in vitro cardiac toxicity compared to the lead compound. Functional assays confirmed the agonist activity of key derivatives, while safety evaluations revealed low cytotoxicity and minimal off-target receptor interactions. Collectively, these findings support compound 2 as a promising candidate for further preclinical development in S1R-related CNS disorders. Full article

Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in vitro screening. Methods: Tumor cell proliferation and spreading were investigated using immortalized human cancer and normal cell lines. Angiogenesis was also evaluated in mouse endothelial cells using a tube formation assay. Results: The dual-ligand compound exhibited superior potency in suppressing both uveal and cutaneous melanoma cell viability compared to other cancer cell types or normal cells. Melanoma selectivity reflected inhibition of the HDAC-dependent epigenetic regulation of tumor proliferative kinetics, without involvement of σR signaling. In contrast, the bifunctional compound inhibited the formation of capillary-like structures, formed by endothelial cells, and tumor cell spreading through the specific regulation of σ₁R signaling, but not HDAC activity. Conclusions: Together, the present findings suggest that dual-targeted HDAC/σ₁R ligands might efficiently and simultaneously disrupt tumor growth, dissemination and angiogenesis in melanoma, a strategy amenable to future clinical applications in precision cancer treatment. Full article

Sigma-1R (S1R) is a ubiquitously distributed protein highly expressed in the brain and liver. It acts as a ligand-inducible chaperone protein localized at the endoplasmic reticulum. S1R participates in several signaling pathways that oversee diverse cellular and neurological functions, such as calcium and proteome homeostasis, neuronal activity, memory, and emotional regulation. Despite its crucial functions, S1R expression profile in the brain with respect to age and sex remains elusive. To shed light on this matter, we assessed S1R distribution in the mouse brain across different developmental stages, including juvenile, early adult, and middle-aged mice. Using immunohistochemistry, we found that S1R is predominantly expressed in the hippocampus in juvenile mice, particularly in CA1 and CA3 regions. Notably, S1R is not expressed in the subgranular layer of the dentate gyrus of juvenile mice. We observed dynamic changes in S1R levels during development, with most brain regions showing either an abrupt or gradual decline as mice transition from juveniles to adults. Sexual dimorphism is observed before puberty in the hippocampus and hypothalamus and during adulthood in the hippocampus and cortex. Full article

The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. Despite its importance in physiology and disease, the biological function of S1R is poorly understood. To gain insight into the biological and signaling functions of S1R, we took advantage of recently reported crystal structures of human and Xenopus S1Rs and performed structural modeling of S1R interactions with ligands and cholesterol in the presence of the membrane. By combining bioinformatics analysis of S1R sequence and structural modelling approaches, we proposed a model that suggests that S1R may exist in two distinct conformations—“dynamic monomer” (DM) and “anchored monomer” (AM). We further propose that equilibrium between AM and DM conformations of S1R is essential for its biological function in cells, with AM conformation facilitating the oligomerization of S1R and DM conformation facilitating deoligomerization. Consistent with experimental evidence, our hypothesis predicts that increased levels of membrane cholesterol and S1R antagonists should promote the oligomeric state of S1R, but S1R agonists and pathogenic mutations should promote its deoligomerization. Obtained results provide mechanistic insights into signaling functions of S1R in cells, and the proposed model may help to explain neuroprotective effects of S1R modulators. Full article

Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine. Full article

Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABA_A receptor’s benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABA_A receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABA_ARs-dependent pharmacological effects. Full article

Neurodegeneration is a slow and progressive loss of neuronal cells or their function in specific regions of the brain or in the peripheral system. Among several causes responsible for the most common neurodegenerative diseases (NDDs), cholinergic/dopaminergic pathways, but also some endogenous receptors, are often involved. In this context, sigma 1 receptor (S1R) modulators can be used as neuroprotective and antiamnesic agents. Herein, we describe the identification of novel S1R ligands endowed with antioxidant properties, potentially useful as neuroprotective agents. We also computationally assessed how the most promising compounds might interact with the S1R protein’s binding sites. The in silico predicted ADME properties suggested that they could be able to cross the brain-blood-barrier (BBB), and to reach the targets. Finally, the observation that at least two novel ifenprodil analogues (5d and 5i) induce an increase of the mRNA levels of the antioxidant NRF2 and SOD1 genes in SH-SY5Y cells suggests that they might be effective agents for protecting neurons against oxidative damage. Full article

Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer’s disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative status of the malignant cells. Recently, S2R was reported to be the transmembrane protein TMEM97. Prior to that, we had been investigating the translocator protein (TSPO) as a potential 21.5 kDa S2R candidate protein with reported heme and sterol associations. Here, we investigate the contributions of TMEM97 and TSPO to S2R activity in MCF7 breast adenocarcinoma and MIA PaCa-2 (MP) pancreatic carcinoma cells. Additionally, the role of the reported S2R-interacting partner PGRMC1 was also elucidated. Proximity ligation assays and co-immunoprecipitation show a functional association between S2R and TSPO. Moreover, a close physical colocalization of TMEM97 and TSPO was found in MP cells. In MCF7 cells, co-immunoprecipitation only occurred with TMEM97 but not with PGRMC1, which was further confirmed by confocal microscopy experiments. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduced co-immunoprecipitation of both TMEM97 and PGRMC1 in immune pellets of immunoprecipitated TSPO in MP cells. To the best of our knowledge, this is the first suggestion of a (functional) interaction between TSPO and TMEM97 that can be affected by S2R ligands. Full article

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration. Full article

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418—a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer’s disease (AD). Full article

Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases. Full article

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones. Full article

The opioid peptide β-endorphin coexists in the pituitary and brain in its ^αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (σ1R) displayed positive effects. Thus, ^αN-acetyl β-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, ^αN-acetyl β-Endorphin reduced the analgesia of morphine, β-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by β-Endorphin and absent in σ1R^−/− mice. We observed that σ1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, β-Endorphin promoted the exchange of σ2Rs by G proteins at σ1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the ^αN-acetyl derivative, as σ1R oligomerization decreased and σ2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological β-Endorphin-specific epsilon receptor is a σ1R-regulated MOR and that β-Endorphin and ^αN-acetyl β-Endorphin are endogenous ligands of σ1R. Full article