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Here, we describe the characterization of a radioligand selective for GluN2B‐containing NMDA receptors, 3‐[3H] 1‐(azetidin‐1‐yl)‐2‐(6‐(4‐fluoro‐3‐methyl‐phenyl)pyrrolo[3,2‐b]pyridin‐1‐yl)ethanone ([3H]‐JNJ‐ GluN2B‐5). In rat cortical membranes, the compound bound to a single site, and the following kinetic parameters were measured; association rate constant Kon = 0.0066 ± 0.0006 min−1 nM−1, dissociation rate constant Koff = 0.0210 ± 0.0001 min−1 indicating calculated KD = Koff/Kon = 3.3 ± 0.4 nM, (mean ± SEM, n = 3). The equilibrium dissociation constant determined from saturation binding experiments in rat cortex was KD of 2.6 ± 0.3 nM (mean ± SEM, n = 3). In contrast to the widely used GluN2B radioligand [3H]‐Ro 25‐6981, whose affinity Ki for sigma 1 and sigma 2 receptors are 2 and 189 nM, respectively, [3H]‐JNJ‐GluN2B‐5 exhibits no measurable affinity for sigma 1 and sigma 2 receptors (Ki > 10 μM for both) providing distinct selectivity advantages. Anatomical distribution of [3H]‐JNJ‐GluN2B‐5 binding sites in rat, mouse, dog, monkey, and human brain tissue was studied using in vitro autoradiography, which showed high specific binding in the hippocampus and cortex and negligible binding in the cerebellum. Enhanced selectivity for GluN2B‐containing receptors translated to a good signal‐to‐noise ratio in both in vitro radioligand binding and in vitro autoradiography assays. In conclusion, [3H]‐JNJ‐GluN2B‐5 is a high‐affinity GluN2B radioligand with excellent signal‐to‐noise ratio and unprecedented selectivity. [ABSTRACT FROM AUTHOR]

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs. [ABSTRACT FROM AUTHOR]

By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ1 subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field. [ABSTRACT FROM AUTHOR]

This study investigated the association of sigma receptors (SRs) and their selective ligands (because the molecular characteristics of the same SRs, particularly sigma-2 receptor {S2R}, are not completely clear) in carcinogenesis, their potential use as antitumor agents, and their great utility in tumor imaging. The ion channels and transporters enhance the cell's ability to adapt to the metabolic conditions encountered in the tumor tissue. The high expression of SRs in the proliferating cells compared with those at rest indicates that this is a significant clinical biomarker for determining the proliferative status of solid tumors using functional PET imaging techniques. The association of SRs in the pathophysiology of cancer cells is a result of the high concentration of S1R and S2R binding sites observed in various tumor cell lines and tissues. It would also be remarkable to determine if SRs are involved in metastasis and other metastatic cell behaviors such as adhesion, secretion, motility, and penetration. An absolute challenge for research in this field is to develop an integrated model that describes the molecular mechanisms of sigma receptors, incorporating their known biological and pathophysiological roles., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fotakopoulos et al.)

Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein–protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine. [ABSTRACT FROM AUTHOR]

Here, we describe the characterization of a radioligand selective for GluN2B-containing NMDA receptors, 3-[ 3 H] 1-(azetidin-1-yl)-2-(6-(4-fluoro-3-methyl-phenyl)pyrrolo[3,2-b]pyridin-1-yl)ethanone ([ 3 H]-JNJ- GluN2B-5). In rat cortical membranes, the compound bound to a single site, and the following kinetic parameters were measured; association rate constant K on  = 0.0066 ± 0.0006 min -1  nM -1 , dissociation rate constant K off  = 0.0210 ± 0.0001 min -1 indicating calculated K D  = K off /K on  = 3.3 ± 0.4 nM, (mean ± SEM, n = 3). The equilibrium dissociation constant determined from saturation binding experiments in rat cortex was K D of 2.6 ± 0.3 nM (mean ± SEM, n = 3). In contrast to the widely used GluN2B radioligand [ 3 H]-Ro 25-6981, whose affinity K i for sigma 1 and sigma 2 receptors are 2 and 189 nM, respectively, [ 3 H]-JNJ-GluN2B-5 exhibits no measurable affinity for sigma 1 and sigma 2 receptors (K i  > 10 μM for both) providing distinct selectivity advantages. Anatomical distribution of [ 3 H]-JNJ-GluN2B-5 binding sites in rat, mouse, dog, monkey, and human brain tissue was studied using in vitro autoradiography, which showed high specific binding in the hippocampus and cortex and negligible binding in the cerebellum. Enhanced selectivity for GluN2B-containing receptors translated to a good signal-to-noise ratio in both in vitro radioligand binding and in vitro autoradiography assays. In conclusion, [ 3 H]-JNJ-GluN2B-5 is a high-affinity GluN2B radioligand with excellent signal-to-noise ratio and unprecedented selectivity., (© 2024 International Society for Neurochemistry.)

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy. [ABSTRACT FROM AUTHOR]

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.

Purpose: Memantine is an approved drug for the treatment of Alzheimer’s disease (AD). Autophagy, lysosome dysfunction, and sigma receptors have possible roles in the pathophysiology of AD. Therefore, we aimed to investigate the contribution of sigma receptors and lysosome inhibition to the neuroprotective effects of memantine against amyloid-beta (Aβ)-induced neurotoxicity in SH-SY5Y cells. Methods: We determined the neuroprotective effects of memantine (2.5 µM), dizocilpine (MK801, as a selective N-methyl-D-aspartate (NMDA) receptor antagonist) (5 μM) against Aβ25– 35 (2 μg/μL)-induced neurotoxicity. We used chloroquine (10, 20, and 40 μM) as a lysosome inhibitor and BD-1063 (1, 10, and 30 μM) as a selective sigma receptor antagonist. The MTT assay was used to measure the neurotoxicity in the SH-SY5Y cells. Data were analyzed using the one-way ANOVA. Results: Memantine (2.5 µM), dizocilpine (5 µM), chloroquine (10 and 20 µM) and BD-1063 (1, 10 and 30 µM) decreased the neurotoxic effects of Aβ on the SH-SY5Y cells. However, chloroquine (40 µM) increased the neurotoxic effects of Aβ. Cell viability in the cells treated with memantine + Aβ + chloroquine (10, 20, and 40 μM) was significantly lower than the memantine + Aβ-treated group. Moreover, cell viability in the memantine + Aβ group was higher than the memantine + Aβ + BD-1063 (10 and 30 μM) groups. Conclusion: The lysosomal and sigma receptors may contribute to the neuroprotective mechanism of memantine and other NMDA receptor antagonists. Moreover, the restoration of lysosomes function and the modulation of sigma receptors are potential targets in the treatment of AD.

Background: Alzheimer's disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective: The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions: CT1812 safely works to displace Aβ however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing. [ABSTRACT FROM AUTHOR]

By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ1 subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field.

By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ 1 subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field.

Purpose: Memantine is an approved drug for the treatment of Alzheimer's disease (AD). Autophagy, lysosome dysfunction, and sigma receptors have possible roles in the pathophysiology of AD. Therefore, we aimed to investigate the contribution of sigma receptors and lysosome inhibition to the neuroprotective effects of memantine against amyloid-beta (Aβ)-induced neurotoxicity in SH-SY5Y cells. Methods: We determined the neuroprotective effects of memantine (2.5 µM), dizocilpine (MK801, as a selective N-methyl-D-aspartate (NMDA) receptor antagonist) (5 μM) against Aβ25– 35 (2 μg/μL)-induced neurotoxicity. We used chloroquine (10, 20, and 40 μM) as a lysosome inhibitor and BD-1063 (1, 10, and 30 μM) as a selective sigma receptor antagonist. The MTT assay was used to measure the neurotoxicity in the SH-SY5Y cells. Data were analyzed using the one-way ANOVA. Results: Memantine (2.5 µM), dizocilpine (5 µM), chloroquine (10 and 20 µM) and BD-1063 (1, 10 and 30 µM) decreased the neurotoxic effects of Aβ on the SH-SY5Y cells. However, chloroquine (40 µM) increased the neurotoxic effects of Aβ. Cell viability in the cells treated with memantine + Aβ + chloroquine (10, 20, and 40 μM) was significantly lower than the memantine + Aβ-treated group. Moreover, cell viability in the memantine + Aβ group was higher than the memantine + Aβ + BD-1063 (10 and 30 μM) groups. Conclusion: The lysosomal and sigma receptors may contribute to the neuroprotective mechanism of memantine and other NMDA receptor antagonists. Moreover, the restoration of lysosomes function and the modulation of sigma receptors are potential targets in the treatment of AD. [ABSTRACT FROM AUTHOR]

Sigma receptors are protein chaperones with the unexpected characteristic of being activated by ligand binding. As such, they represent intriguing new targets for potential drug development. As a protein chaperone, these "receptors" escort proteins from the endoplasmic reticulum to their destinations and act to correct misfolded proteins. The two subtypes of sigma receptors, named σ1 and σ2, are markedly distinct from each other. Agonists and antagonists at these receptors show promise as new drug targets, addressing a range of diseases including neurodegenerative disorders, cancer, and cardiac disorders, and may also be analgesic agents and rehabilitation drugs for opioid use disorder. As an analgesic, sigma receptors seem to be more effective in treating neuropathic than nociceptive pain. New bifunctional compounds are being developed with opioids, because agents targeting sigma receptors may have an opioid-sparing effect. The pipeline of agents based on the sigma receptors is long and may treat things from Fragile X syndrome to Parkinson's disease to Huntington's disease to cancer. A novel agent ADV502 acts as a high-affinity σ1 antagonist and partial agonist at the µ-opioid receptor and may be an important agent both for the treatment of neuropathic cancer pain and for rehabilitation of opioid use disorder. Since there has been little recent innovation in pain medicine regarding new compounds and drug targets, drugs that affect the sigma receptor system seem promising and encouraging., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Pergolizzi Jr et al.)

Integrated modeling of the pharmacokinetic (PK) and target binding, by means of a TMDD model, can provide valuable insights into the expected pharmacodynamic (PD) effects of monoclonal antibodies (mAbs). Optimal characterization of the human PK and target binding for mAbs requires data obtained after intravenous (IV) administration which can be combined with subcutaneous (SC) data to further this characterization. Integration of free and/or total target measurements in a population TMDD model will allow quantification of target engagement which is the first step in the cascade leading to efficacy. However, the assays for determination of free target concentrations are analytically challenging and are inherently biased to overpredict the true concentrations in the presence of mAb:target complexes. For that reason, the objective of the current research was to evaluate the predictive value of free target concentrations in a TMDD model developed using PK and total target observations only. Further, a secondary objective was to demonstrate that prediction of SC data is feasible, based on an existing IV model and typical values of mAb parameters reported for SC absorption. GSK3772847, a human immunoglobulin G2 sigma isotype (IgG2f) mAb that binds to the extracellular domain of the interleukin‐33 receptor (IL‐33R or ST2) and neutralizes IL‐33‐mediated ST2 signaling, was used as a model compound for mAbs in this study. [ABSTRACT FROM AUTHOR]

Despite the interest aroused by sigma receptors (SRs) in the area of oncology, their role in tumor biology remains enigmatic. The predominant subcellular localization and main site of activity of SRs are the endoplasmic reticulum (ER). Current literature data, including recent findings on the sigma 2 receptor subtype (S2R) identity, suggest that SRs may play a role as ER stress gatekeepers. Although SR endogenous ligands are still unknown, a wide series of structurally unrelated compounds able to bind SRs have been identified. Currently, the identification of novel antiproliferative molecules acting via SR interaction is a challenging task for both academia and industry, as shown by the fact that novel anticancer drugs targeting SRs are in the preclinical-stage pipeline of pharmaceutical companies (i.e., Anavex Corp. and Accuronix). So far, no clinically available anticancer drugs targeting SRs are still available. The present review focuses literature advancements and provides a state-of-the-art overview of SRs, with emphasis on their involvement in cancer biology and on the role of SR modulators as anticancer agents. Findings from preclinical studies on novel anticancer drugs targeting SRs are presented in brief.

More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The sigma-1 and sigma-2 receptors were first discovered in the 1960s and were thought to be a form of opioid receptors initially. Over time, more was gradually learned about these receptors, which are actually protein chaperones, and many of their unique or unusual properties can contribute to a range of important new therapeutic applications. These sigma receptors translocate in the body and regulate calcium homeostasis and mitochondrial bioenergetics and they also have neuroprotective effects. The ligands to which these sigma receptors respond are several and dissimilar, including neurosteroids, neuroleptics, and cocaine. There is controversy as to their endogenous ligands. Sigma receptors are also involved in the complex processes of cholesterol homeostasis and protein folding. While previous work on this topic has been limited, research has been conducted in multiple disease states, such as addiction, aging. Alzheimer's disease, cancer, psychiatric disorders, pain and neuropathic pain, Parkinson's disease, and others. There is currently increasing interest in sigma-1 and sigma-2 receptors as they provide potential therapeutic targets for many disease indications., Competing Interests: Mark Coleman is on the Board of Directors of Axome Therapeutics. Joseph V. Perolizzi is the Executive Chairman and President of Advantx Pharmaceuticals, Inc., (Copyright © 2023, Pergolizzi et al.)