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Introduction to Cancer, Conventional Therapies, and Bionano-Based Advanced Anticancer Strategies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
An example of a tumor-specific receptor is the sigma receptor, which was first described as an opioid receptor, but later found to have the ability to bind to various drugs. Sigma receptors are notably upregulated in cancer cells and tumor tissues. Drugs that target sigma receptors, particularly sigma 2 receptors, showed to have anti-proliferative effects. One possibility is that drugs that target sigma receptors could have anti-cancerous effects through the modulation of ion channels, as well as other metastatic cellular behaviors could also be affected, such as motility, adhesion, and secretion [106].
Antipsychotics: pharmacology
Published in Kathy J Aitchison, Karena Meehan, Robin M Murray, First Episode Psychosis, 2021
Kathy J Aitchison, Karena Meehan, Robin M Murray
Another suggestion involves the modulation of dopaminergic transmission by sigma receptor blockade; a selective sigma antagonist has been claimed to show a beneficial effect on the negative symptoms of schizophrenia.136
The Mechanisms Behind Tumour Repopulation
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
Another potential group of tumour proliferation-specific radiopharmaceuticals are radiolabelled sigma-2 receptor ligands. Sigma receptors are complex proteins that are involved in several aspects of cancer pathology. In vitro studies showed that the overexpression of sigma receptors in proliferating cells can be up to 10 times higher than in quiescent cells (Wheeler et al. 2000), which is a reason why radiolabelled ligands that bind to sigma-2 receptors are currently tested for PET imaging to provide a quantitative assessment of cell proliferation. A number of studies indicated that PET imaging with radiolabelled sigma-2 receptor ligands can offer superior tumour specific information compared to TK-1 based radiotracer imaging (Rowland et al. 2006; Mach, Dehdashti & Wheeler 2009). Carbon-11 as well as 18F-labelled sigma receptor ligands have been investigated with different results (Mach, Dehdashti & Wheeler 2009). A disadvantage of 11C-labelled compounds is the short half-life of 11C (20.38 min), which limits its clinical utility, despite the high tumour uptake and good image contrast showed by in vivo studies (Mach, Dehdashti & Wheeler 2009).
Sigma receptor ligands haloperidol and ifenprodil attenuate hypoxia induced dopamine release in rat striatum
Published in Neurological Research, 2022
Murat Gursoy, Zulfiye Gul, R. Levent Buyukuysal
Interaction of the sigma ligands with NMDA receptors seems to be a major problem in studies using sigma receptor ligands. Since ifenprodil [48] and haloperidol [49] act as an NMDA receptor antagonist, we cannot exclude the possibility that direct blockade of NMDA receptors is involved in inhibitory effects under hypoxic conditions. MK-801, an NMDA receptor antagonist with a negligible affinity for sigma receptors, partially blocked hypoxia-induced dopamine release unlike the non-NMDA receptor antagonist CNQX in present study. When calculating the IC50 values of MK-801 and sigma ligands in blocking the hypoxia-induced dopamine release, we observed that IC50 values of sigma ligands were significantly lower than MK-801 (0.85 μM, 1.06 μM, 2.35 μM for haloperidol, ifenprodil and MK81, respectively). Considering the IC50 values of the sigma receptor ligands and the negligible affinity of NMDA receptor antagonists for the sigma receptors [21,50,51] together, it is likely that sigma receptor ligands probably inhibit hypoxia-induced dopamine release by a mechanism with partial or low level interaction with NMDA receptors.
The sigma-2 (σ-2) receptor: a review of recent patent applications: 2013–2018
Published in Expert Opinion on Therapeutic Patents, 2018
Benjamin E. Blass, John Patrick Rogers
The development of novel science in the sigma receptor space has been a subject of several publications from Patricia Melnyk and her colleagues at the University of Lille [26]. As part of their efforts to explore the role of the sigma receptor in neurodegenerative disease, they recently disclosed a series of sigma-1 and sigma-2 receptor ligands typified by the Markush structure (58) (Figure 14) [27]. Although the primary focus of this work was the identification of highly selective sigma-1 receptor ligands, a number of compounds in the disclosure displayed significant sigma-2 receptor-binding affinity (59–61) (Figure 14). Studies of the highly selective sigma-1 receptor ligand (62) (Figure 14) in an animal model of multiple sclerosis were also disclosed. Specifically, this compound was shown to delay the onset of experimental autoimmune encephalomyelitis (EAE) in mice (10 mg/kg), as well as alleviate symptoms in mice with established EAE (10 mg/kg). Application of this technology to the treatment of other neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis was also claimed as part of the invention.
Advances with the discovery and development of novel sigma 1 receptor antagonists for the management of pain
Published in Expert Opinion on Drug Discovery, 2023
Mallory Burns, Nicholas Guadagnoli, Christopher R. McCurdy
In the relatively short history of sigma receptors, outlined in Figure 1, S1Rs have proven to be a unique target for pain modulation [40]. First identified in 1976 as an opioid receptor subtype, just six years later in 1982 sigma receptors were proven to be unique non-opioid proteins due to the differences in binding affinity for benzomorphans and their low affinity for the opioid antagonist naltrexone [15,41,42]. However, to this day, they are still often mistaken as belonging to the opioid receptor family. Opioid receptors show binding preference for (-)-benzomorphans, whereas sigma receptors show higher affinity for (+)-benzomorphans [16,42]. Additionally, the classic opioid antagonist naltrexone shows low affinity for sigma receptors and is unable to antagonize sigma receptors [43]. The next major milestone in sigma receptor history was the distinction of the two receptor subtypes, sigma-1 and sigma-2, now known to vary in protein size, tissue distribution, pharmacology, and ligand binding profiles [17,44,45]. In 1996, the sigma-1 receptor was first cloned from guinea pig, followed by human, mouse, and rat tissue, and the amino acid sequence confirmed their distinctness from opioid receptors along with any relation to other mammalian proteins [1,21,46–48]. The sigma-2 receptor would not be sequenced until 2017, and the co-crystal structure was published in 2021, thus making research on sigma-1 drug development more accessible and desirable [49,50]. The creation of S1R knockout (KO) mice in 2003 enabled the field of sigma-1 research to make huge progress in terms of understanding the physiological and pathological role S1Rs have in normal and disordered conditions [51]. The last 20 years in particular have seen a significant increase in sigma receptor research, with publications increasing from approximately 1,200 in 2006 to over 4,300 in 2022 [52]. During this time, milestones such as the official characterization of S1Rs as chaperone proteins, the S1R co-crystal structure, and notable clinical trials for both S1R agonists and antagonists have occurred [53].