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Pharmaceuticals
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Current Advances in Therapeutic Potential of Sigma Receptor Ligands
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Current Advances in Therapeutic Potential of Sigma Receptor Ligands

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 September 2025 | Viewed by 3665

Special Issue Editors

Dr. Maria Dichiara

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: medicinal chemistry; synthesis; anticancer; analgesia; hybrid compounds; statistical analysis
Dr. Emanuele Amata

E-Mail Website
Guest Editor
Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
Interests: medicinal chemistry; cancer; databases; QSAR; chemical synthesis; radioligand binding assay; sigma receptor
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although nearly 50 years have passed since their first description as opioid receptors, the field of sigma receptors continues to pique considerable interest. Both proteins predominantly localize in the endoplasmic reticulum and are considered orphan receptors, with implications spanning over a diverse range of conditions. The sigma-1 receptor exhibits a trimeric architecture, and it works as a chaperone protein at the endoplasmic reticulum−mitochondria interface, regulating Ca2+ signaling and cell survival. The sigma-1 receptor agonists show neuroprotective, antiamnestic, and antidepressant effects, while the antagonists have modulatory effects on opioid analgesia, alongside antiproliferative and antiangiogenic activities.

The molecular identity of the sigma-2 receptor has more recently been determined as TMEM97, a regulator of the sterol transporter NPC1. The sigma-2 receptor is found in lungs, liver, and kidney, and it is highly expressed in several malignant tumors.

These findings suggest the potential of pharmacological modulation of sigma receptors to yield useful drugs across various conditions. In this context, the present special issue aims to collect both original research articles and comprehensive reviews concerning the development of sigma receptor ligands and associated efforts toward their therapeutic applications.

Dr. Maria Dichiara
Dr. Emanuele Amata
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sigma-1 receptor
  • sigma-2 receptor
  • TMEM97
  • cancer, neurodegeneration
  • neuroprotection
  • pain
  • CNS disorders
  • SAR

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Published Papers (3 papers)

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Research

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18 pages, 5244 KiB  
Article
Hypidone Hydrochloride (YL-0919), a Sigma-1 Receptor Agonist, Improves Attention by Increasing BDNF in mPFC
by Yixin Yang, Yue Zhang, Xiaojuan Hou, Hailong Li, Hui Ma and Yunfeng Li
Pharmaceuticals 2025, 18(4), 455; https://doi.org/10.3390/ph18040455 - 24 Mar 2025
Viewed by 558
Abstract
Background/Objectives: The available treatment for attention deficit is drug therapy, but the drugs show poor adverse effect profiles and individual variability in response, especially in adults. Hypidone hydrochloride (YL-0919) is a selective sigma-1 receptor agonist that demonstrated a faster onset antidepressant effect in [...] Read more.
Background/Objectives: The available treatment for attention deficit is drug therapy, but the drugs show poor adverse effect profiles and individual variability in response, especially in adults. Hypidone hydrochloride (YL-0919) is a selective sigma-1 receptor agonist that demonstrated a faster onset antidepressant effect in our previous studies. Current studies aim to study the attention-enhancing effect and mechanism of YL-0919. Methods: We used the five-choice serial reaction time task (5-CSRTT) to measure the attention-improving effect of YL-0919 in SD rats under a physiological state and exogenous corticosterone (CORT)-exposed state. The depression/anxiety-like behavioral experiments were used in the CORT-exposed rats. Immunofluorescence staining, western blotting, and Golgi–Cox staining were used to investigate the attention-improving mechanism of YL-0919. Results: The studies found that intragastric administration of 2.5 and 5 mg/kg YL-0919 for 6 days significantly improved the attention of SD rats under a physiological state. CORT exposure caused depression/anxiety-like behaviors and attention deficit in the rats. Intragastric administration of 3 mg/kg SA4503 or 2.5 and 5 mg/kg YL-0919 for 6 days significantly alleviated attention deficit in SD rats under an exogenous CORT-exposed state. In addition, YL-0919 administration obviously increased the expression of BDNF, PSD95, and synapsin1 and improved the dendritic complexity and the dendritic spine density in the medial prefrontal cortex (mPFC). Conclusions: These results reveal that YL-0919 as a selective sigma-1 receptor agonist can significantly improve the attention of SD rats under a physiological state and exogenous CORT-exposed state. Improving the level of BDNF and dendritic complexity in the mPFC may be the important mechanisms of YL-0919 to improve attention. The study also provides a potential novel target for the drug therapy of attention deficit. Full article
(This article belongs to the Special Issue Current Advances in Therapeutic Potential of Sigma Receptor Ligands)
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19 pages, 17773 KiB  
Article
SA4503 Mitigates Adriamycin-Induced Nephropathy via Sigma-1 Receptor in Animal and Cell-Based Models
by Hideaki Tagashira, Shinsuke Chida, Md. Shenuarin Bhuiyan, Kohji Fukunaga and Tomohiro Numata
Pharmaceuticals 2025, 18(2), 172; https://doi.org/10.3390/ph18020172 - 27 Jan 2025
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Abstract
Background/Objectives: The Sigma-1 receptor (Sigmar1), an intracellular chaperone protein, is ubiquitously expressed throughout the body, but its role in peripheral organs, such as the kidneys, remains unclear. Here, we investigated the protective effects and molecular mechanisms of SA4503, a selective Sigmar1 agonist, on [...] Read more.
Background/Objectives: The Sigma-1 receptor (Sigmar1), an intracellular chaperone protein, is ubiquitously expressed throughout the body, but its role in peripheral organs, such as the kidneys, remains unclear. Here, we investigated the protective effects and molecular mechanisms of SA4503, a selective Sigmar1 agonist, on Adriamycin (ADR)-induced renal glomerular injury. Methods: Using in vitro and in vivo models, we evaluated the effects of SA4503 on ADR-induced podocyte injury, including podocyte survival, albumin permeability, urinary albumin levels, and Sigmar1-nephrin interactions. NE-100, a Sigmar1 antagonist, was co-administered to validate the specificity of the effects of SA4503. Results: Sigmar1 was highly expressed in podocytes and mouse kidney tissues. SA4503 significantly reduced ADR-induced podocyte injury and urinary albumin leakage in mice. Mechanistically, SA4503 preserved Sigmar1-nephrin interactions, which were disrupted in ADR-treated kidneys. This protective effect was abolished by NE-100 co-treatment, confirming the Sigmar1-dependency of SA4503’s action. Conclusions: These findings demonstrate that the activation of Sigmar1 by SA4503 protects against ADR-induced podocyte injury and glomerular damage, likely by stabilizing Sigmar1-nephrin interactions. Therefore, Sigmar1 represents a promising therapeutic target for glomerular diseases such as nephrotic syndrome. Full article
(This article belongs to the Special Issue Current Advances in Therapeutic Potential of Sigma Receptor Ligands)
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Review

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28 pages, 9306 KiB  
Review
Repurposing Sigma-1 Receptor-Targeting Drugs for Therapeutic Advances in Neurodegenerative Disorders
by Kiarash Eskandari, Sara-Maude Bélanger, Véronik Lachance and Saïd Kourrich
Pharmaceuticals 2025, 18(5), 700; https://doi.org/10.3390/ph18050700 - 9 May 2025
Cited by 1 | Viewed by 1347
Abstract
Neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as [...] Read more.
Neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration. Full article
(This article belongs to the Special Issue Current Advances in Therapeutic Potential of Sigma Receptor Ligands)
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