Sigma receptors: recent advances and new clinical potentials

doi:10.1016/S0031-6865(99)00034-5

Pharmaceutica Acta Helvetiae

Volume 74, Issues 2–3, March 2000, Pages 211-218

Pharmaceutica Acta H...

https://doi.org/10.1016/S0031-6865(99)00034-5 Get rights and content

Abstract

Several recent advances are leading to a better understanding of sigma receptors. Here we focus on our recent findings regarding cellular functions of sigma-2 receptors and discuss their possible clinical implications. Agonists at sigma-2 receptors induced changes in cell morphology and apoptosis in various cell types. Sigma-2 receptor activation produced both transient and sustained increases in [Ca⁺⁺]i, derived from different intracellular stores. These changes in [Ca⁺⁺]i and cytotoxic effects are mediated by intracellular sigma-2 receptors. Sigma-2 agonists induced apoptosis in drug-resistant cancer cells, enhanced the potency of DNA damaging agents, and down-regulated expression of p-glycoprotein mRNA. Thus, sigma-2 receptor agonists may be useful in treatment of drug-resistant cancers. Sigma radioligands have been used in tumor imaging. We also discuss how sigma-2 antagonists might prevent the irreversible motor side effects of typical neuroleptics. Sigma-2 receptors may subserve a novel signalling pathway to apoptosis, involved in regulation of cell proliferation and/or viability.

Section snippets

General introduction

Sigma receptors are high affinity binding sites for many drugs with psychotropic activity (Walker et al., 1990). Initially proposed as a subtype of opioid receptor (Martin et al., 1976), and then confused with phencyclidine binding sites on the NMDA receptor channel, subsequent studies by many groups led to reclassification of these binding sites as unique entities unlike any other known neurotransmitter or hormone receptor (Quirion et al., 1987). Much of the initial interest in sigma receptors

Functions of sigma-1 receptors

The most well-studied of the sigma receptor subtypes is the sigma-1 receptor. Several functions for sigma-1 receptors have been uncovered. These will not be reviewed in detail here, but some of these include: (1) modulation of synthesis and release of dopamine (Booth and Baldessarini, 1991; Patrick et al., 1993) and acetylcholine (Matsuno et al., 1995), (2) modulation of NMDA-type glutamate receptor electrophysiology (Monnet et al., 1992), (3) modulation of NMDA-stimulated neurotransmitter

Functions of sigma-2 receptors

Our studies have focused on sigma-2 receptors. In particular, we have investigated the possible role of sigma-2 receptors in regulation of cell proliferation and maintenance of cell viability. Results from previous brain microinjection studies suggested that some sigma ligands might be neurotoxic, since reduced haloperidol (a major haloperidol metabolite and potent sigma ligand) and the cyclohexane diamine, BD614 caused extensive gliosis and loss of magnocellular neurons in and around the

Clinical potentials for sigma-2 receptors

Sigma-2 receptor-mediated induction of morphology changes and apoptotic cell death may have important implications for the treatment of psychoses. Sigma receptors occur in high density in regions of the brain which control motor behavior. Cerebellum, substantia nigra, red nucleus, and the brainstem cranial nerve nuclei are areas with very high density of sigma receptors (Walker et al., 1990). Based on the ability of various sigma ligands to induce motor anomalies in rats upon microinjection

Overall summary and conclusion

Sigma-2 receptors may represent components of a novel apoptotic pathway which could play a role in regulation of cell proliferation or in development. This pathway consists of intracellular membrane bound sigma-2 receptors, localized on organelles known to store calcium (endoplasmic reticulum and mitochondria) and with the ability to cause release of calcium from these stores. Calcium signals may be utilized in normal cell signalling and/or for the induction of apoptosis. Elucidation of the

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Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K_iσ₁R = 38 ± 3.7; K_iσ₂R = 2917 ± 769 and HDACs IC₅₀ = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC₅₀ of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ₁R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.
Photoaffinity labeling approaches to elucidate lipid–protein interactions
2022, Current Opinion in Chemical Biology
Lipid–protein interactions serve as the basis for many of the diverse roles of lipids. However, these noncovalent binding events are often weak, transient, or dependent upon environmental cues. Photoaffinity labeling can preserve these interactions under native conditions, enabling their biochemical profiling. Typically, photoaffinity labeling probes contain a diazirine photocrosslinker and a click chemistry handle for enrichment and downstream analysis. In this review, we summarize recent advances in the understanding the mechanisms of diazirine photocrosslinking, and we provide an overview of recent applications of photoaffinity labeling to reveal the interactions of diverse types of lipids with specific members of the proteome.
Brain-derived neurotrophic factor for high-throughput evaluation of selective Sigma-1 receptor ligands
2022, Journal of Pharmacological and Toxicological Methods
The Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone protein that has been implicated in attenuating inflammatory stress-mediated brain injuries. Selective S1R agonists represent a new class of therapeutic agent for treating neuropsychiatric and neurodegenerative disorders, however, to date, no S1R ligand has been approved for therapeutic purposes. We used three potential methods on known and potential S1R ligands to develop an unambiguous high-throughput cell screen for S1R activity. We screened known and potential S1R ligands using radioligand binding and previously reported markers of S1R activity including BDNF release, modulation of IP₃ mediated calcium release, and modulation of NGF-induced neurite sprouting. Here, we present results several prototypical S1R compounds and some compounds with the potential for drug repurposing. Using an in-situ ELISA approach we demonstrated that these compounds could stimulate S1R-mediated BDNF release, which is a valuable therapeutic property since BDNF plays a critical role in neuronal support. These compounds were classified as S1R agonists because the BDNF response was comparable to the prototypical agonist 4-PPBP and because it could be reversed by a S1R selective concentration of the antagonist BD1063. When modulation of IP₃ mediated calcium response and NGF-induced neurite sprouting were used as a measure of S1R activation, we were unable to reproduce the published results and determined that they are not reliable measures for evaluating functional properties of S1R ligands.
Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents
2019, European Journal of Medicinal Chemistry
Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
SYA 013 analogs as moderately selective sigma-2 (σ<inf>2</inf>) ligands: Structure-affinity relationship studies
2019, Bioorganic and Medicinal Chemistry
Several lines of evidence suggest that selective sigma-2 (σ₂) ligands might be useful for the treatment of solid tumors. However, very few selective σ₂ ligands have been identified. This study was aimed at identifying new selective σ₂ receptor ligands using a previously identified agent, SYA 013 as a lead. Four groups, homopiperazine, piperazine, tropane and selected oxime analogs of the homopiperazines were identified, synthesized and subsequently screened at the σ₁ and σ₂ receptors. The results demonstrate that these scaffolds can be modified to obtain selective σ₂ receptor ligands. 1-(5-Chloropyridin-2-yl)-4-(3-((4-fluorophenyl)thio)propyl)-1,4-diazepane, 7 and 3-(4-chlorophenyl)-8-(3-((2-fluorophenyl)thio)propyl)-8-azabicyclo[3.2.1]octan-3-ol, 21 were identified as the highest binding affinity ligands (σ₂Ki = 2.2 nM) and (4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-butan-1-one oxime, 22 as a high affinity and the most selective ligand for the σ₂ receptor (σ₁Ki/σ₂Ki = 41.8).
Benzimidazolone-based selective σ<inf>2</inf> receptor ligands: Synthesis and pharmacological evaluation
2019, European Journal of Medicinal Chemistry
Sigma receptors (σRs) are considered to be a significant and valid target for developing new medications to address several diseases. Their potential involvement in numerous central nervous system disorders, neuropathic pain, addiction, and cancer has been extensively reported. In particular, the σ₂R has been identified as potential target for the development of pharmaceutical agents intended to treat the negative effects associated with drugs of abuse. As a continuation of our previous efforts to develop new selective σ₂R ligands, a series of benzimidazolone derivatives were designed, synthesized, and characterized. The newly synthesized ligands were evaluated through in vitro radioligand binding assays to determine their affinity and selectivity towards both σ₁ and σ₂ receptors. Several derivatives displayed high affinity for the σ₂R (K_i = 0.66–68.5 nM) and varied from preferring to selective, compared to σ₁R (σ₁/σ₂ = 5.8–1139). Among them, compound 1-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-3-propyl-1,3-dihydrobenzimidazol-2-one dihydrochloride (14) displayed the ability to produce a dose-dependent reduction in the convulsive effects of cocaine in a rodent model after injecting 10 mg/kg (i.p.). These preliminary results support the use of selective σ₂R ligands in the development of useful pharmacological tools or potential pharmacotherapies for cocaine toxicity.

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Sigma receptors: recent advances and new clinical potentials

Abstract

Section snippets

General introduction

Functions of sigma-1 receptors

Functions of sigma-2 receptors

Clinical potentials for sigma-2 receptors

Overall summary and conclusion

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Nucl. Med. Biol.

Life Sci.

Brain Res.

Brain Res.

Eur. J. Pharmacol., Mol. Pharmacol. Sect.

J. Biol. Chem.

Nucl. Med. Biol.

Eur. J. Pharmacol.

Psychiatry Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Brain Res.

Cell Calcium

Eur. J. Pharmacol.

Trends Neurosci.

Trends Pharmacol Sci.

Eur. J. Pharmacol., Mol. Pharmacol. Sect.

Eur. J. Pharmacol.

Tardive dyskinesia with inflated neurons of the cerebellar dentate nucleus

Acta Neuropathol. (Berlin)

Overexpression of sigma receptors in non-neural human tumors

Cancer Res.

Sigma receptor-mediated morphological and cytotoxic effects on primary cultures of rat central and peripheral nervous system

Society for Neuroscience Abstracts

Characterization of the enantiomers of cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (BD737 and BD738): novel compounds with high affinity, selectivity, and biological efficacy at sigma receptors

J. Pharmacol. Exp. Ther.

Ibogaine and ibogamine modulate intracellular calcium levels via interaction with sigma-2 receptors

Society for Neuroscience Abstracts

Sigma receptor ligands modulate expression of the multidrug resistance gene in human and rodent brain tumor cell lines

Proceedings of the American Association for Cancer Research

An endogenous ligand for the sigma opioid binding site

Synapse

Sigma-2 receptor activation induces apoptosis in breast, prostate, and neuroblastoma cell lines

Proceedings of the American Association for Cancer Research

Sigma receptor regulation of NMDA-stimulated [3H]arachidonic acid release from cerebellar granule cells is pertussis toxin-sensitive

Society for Neuroscience Abstracts

Purification, molecular cloning, and expression of the mammalian sigma1-binding site

Proc. Natl. Acad. Sci. U.S.A.

Sigma receptor regulation of NMDA-stimulated [ $^{3} H$ ]arachidonic acid release from cerebellar granule cells is pertussis toxin-sensitive

Purification, molecular cloning, and expression of the mammalian sigma₁-binding site