For some time now, the research on sigma receptors has been at a high level of maturity but, despite everything that has already been achieved, further work in this field still holds huge appeal, ...with vast possibilities for original discoveries ...
Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has ...gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.
•Role of σ1in vivo is to allow microglia to leave neuronal injuries.•σ1 Agonists block microglial responses to neuronal injuries.•σ1 Agonists do not affect microglial motility and their ability to ...collect dying neurons.
Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be “switched-off” and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma (σ) receptor activation. Here, we take advantage of the optical transparency of the zebrafish embryo to study the role of σ1 receptor in microglia in an intact living brain. By combining chemical approaches with real time imaging we found that treatment with PB190, a σ1 agonist, blocks microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role of σ1in vivo is to “switch-off” microglia after they responded to an injury allowing for these cells to leave the site of damage. This indicates that pharmacological manipulation of σ1 receptor modulates microglial responses providing new approaches to reduce the devastating impact that microglia have in neurodegenerative diseases.
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.
These unprecedented times have forced the scientific community to gather to face the COVID-19 pandemic. Efforts in diverse directions have been made. A multi-university team has focused on the ...identification of the host (human) proteins interacting with SARS-CoV-2 viral proteins, with the aim of hampering these interactions that may cause severe COVID-19 symptoms. Sigma-1 and sigma-2 receptors surprisingly belong to the "druggable" host proteins found, with the pan-sigma receptor modulator PB28 displaying the most potent anti-SARS-CoV-2 activity in in vitro assays. Being 20-fold more active than hydroxychloroquine, without cardiac side effects, PB28 is a promising antiviral candidate worthy of further investigation. Our research group developed PB28 in 1996 and have thoroughly characterized its biological properties since then. Structure-affinity relationship (SAfiR) studies at the sigma receptor subtypes were also undertaken with PB28 as the lead compound. We herein report our knowledge of PB28 to share information that may help to gain insight into the antiviral action of this compound and sigma receptors, while providing structural hints that may speed up the translation into therapeutics of this class of ligands.
Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to ...overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds,
,
, and
acting as CS-promoting agents. We deepened their CS mechanisms in the "pure" model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors.
Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological ...evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT
, 5-HT
, 5-HT
receptor, and dopamine D
receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood-brain barrier. We identified compound
that combines an affinity profile compatible with antipsychotic activity (5-HT
= 41.5 nM, 5-HT
= 315 nM, 5-HT
= 42.5 nM, D
= 300 nM), and compound
that has an affinity profile consistent with studies in the context of ASD (5-HT
= 23.9 nM, 5-HT
= 39.4 nM, 5-HT
= 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound
, which might be suitable for studies in vivo.
The development of effective drugs to treat coronavirus infections remains a significant challenge for the scientific community. Recent evidence reports on the sigma-1 receptor (S1R) as a key ...druggable host protein in the SARS-CoV-1 and SARS-CoV-2 interactomes and shows a potent antiviral activity against SARS-CoV-2 for the S1R antagonist PB28. To improve PB28 activity, we designed and tested a series of its analogues and identified a compound that is fourfold more potent against SARS-CoV-2 than PB28 itself. Interestingly, we found no direct correlation between S1R affinity and SARS-CoV-2 antiviral activity. Building on this, we employed comparative induced fit docking and molecular dynamics simulations to gain insights into the possible mechanism that occurs when specific ligand-protein interactions take place and that may be responsible for the observed antiviral activity. Our findings offer a possible explanation for the experimental observations, provide insights into the S1R conformational changes upon ligand binding and lay the foundation for the rational design of new S1R ligands with potent antiviral activity against SARS-CoV-2 and likely other viruses.
A new sigma-2 (σ2) receptor ligand (
) was efficiently synthesized and evaluated for cytotoxic, proapoptotic, and antimigratory activity on pancreatic ductal adenocarcinoma (PDAC) primary cell ...cultures, which restrained the aggressive and chemoresistant behavior of PDAC. This compound showed relevant antiproliferative activity with half maximal inhibitory concentration (IC50) values ranging from 0.701 to 0.825 μM. The cytotoxic activity was associated with induction of apoptosis, resulting in apoptotic indexes higher than those observed after exposure to a clinically relevant concentration of the gemcitabine, the first-line drug used against PDAC. Interestingly,
was also able to significantly inhibit the migration rate of both PDAC-1 and PDAC-2 cells in the scratch wound-healing assay. In conclusion, our results support further studies to improve the library of thiosemicarbazones targeting the σ-2 receptor for a deeper understanding of the relationship between the biological activity of these compounds and the development of more efficient anticancer compounds against PDAC.
There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression ...of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propylpiperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells.
The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-5-3-(4-cyclohexylpiperazin-1-yl)propyl-5,6,7,8-tetrahydronaphthalen-5-yloxy-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxyhexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models.
The IC
of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 μM, respectively. A low dose of PB221 (1 μM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 μM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model.
This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.
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