In 2025, the publications featured in the SIGMA-1EUROPE Archives reflected the broad scope of current sigma-1 receptor research – from medicinal chemistry and molecular imaging to cellular mechanisms, experimental disease models, pain, and cognition. Together, these seven publications illustrate how research on the sigma-1 receptor spans fundamental biology, drug discovery and potential therapeutic applications.
Drug discovery, imaging and theranostics
Design and Synthesis of Tetrahydropyrrolo[3,4-c]Pyrazole Sigma-1 Receptor Ligands
Cosentino et al., ChemMedChem, 2025
Cosentino and colleagues developed a new series of tetrahydropyrrolo[3,4-c]pyrazole-based sigma-1 receptor ligands and explored how structural modifications influence receptor affinity and selectivity. Among the compounds studied, AD417 emerged as a promising S1R ligand, while additional assessment of hERG channel inhibition addressed an important safety consideration in the development of sigma receptor-targeting compounds. The study provides a foundation for further optimisation of this scaffold in S1R drug discovery.
Two Targets, One Mission: Heterobivalent Metal-Based Radiopharmaceuticals for Prostate Cancer Imaging and Therapy
Sobral et al., ChemMedChem, 2025
This review explored the development of heterobivalent radiopharmaceuticals designed to target more than one molecular marker in prostate cancer. Among the potential targets discussed was the sigma-1 receptor, alongside established and emerging cancer biomarkers. The authors highlighted how dual-target approaches could contribute to more comprehensive tumour imaging and improved theranostic strategies in heterogeneous disease.
A Full-Spectrum Evaluation of Sigma-1 Receptor (S1R) Positron Emission Tomography (PET) Radioligands from Binding Affinity to Clinical Imaging
Mastropasqua et al., Molecules, 2025
Mastropasqua and colleagues provided a comprehensive overview of S1R PET radioligands developed over the past two decades. The review followed their development from molecular structure, receptor affinity and selectivity through metabolism, pharmacokinetics and in vivo imaging, as well as their potential for clinical translation. It also highlighted the role of PET radioligands not only in visualising S1R in health and disease, but also as tools supporting the development and evaluation of novel S1R-targeting drugs.
Cellular mechanisms and experimental models
Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer
Cagalinec et al., BBA – Molecular Cell Research, 2025
This review focused on mitochondria-associated endoplasmic reticulum membranes (MAMs), specialized contact sites that coordinate processes including calcium signaling, ER stress, lipid exchange, and mitochondrial quality control. Sigma-1 receptors are among the key proteins operating at these sites. The authors examined how disruption of MAM-associated pathways contributes to rare neurodegenerative diseases and cancer, and discussed the possibility of targeting these mechanisms therapeutically.
Generation and phenotypic characterization of a sigma-1 receptor knockout rat
Huerta et al., Life Sciences, 2025
Huerta and colleagues developed and characterized a new sigma-1 receptor knockout rat using CRISPR/Cas9 technology. The animals showed no major developmental or baseline behavioral abnormalities, but displayed changes in selected behaviors and reduced neuropathic pain following nerve injury. The model provides a new experimental tool for investigating the physiological and pathological roles of S1R and for studying therapeutic strategies targeting the receptor.
From pain modulation to cognitive function
Sigma-1 receptor antagonism as a promising strategy for postoperative pain treatment: A study in laparotomized mice
Santos-Caballero et al., Biomedicine & Pharmacotherapy, 2025
Santos-Caballero and colleagues investigated sigma-1 receptor antagonism in a mouse model of postoperative pain. S1R antagonists influenced tactile allodynia through mechanisms involving peripheral opioid signaling, while combining S1R antagonism with morphine enhanced analgesic effects across several components of postoperative pain. Importantly, S1R antagonism did not enhance the effects of morphine on gastrointestinal transit or its rewarding properties in the tests used, supporting further investigation of sigma-1 receptors in opioid-based pain management.
Sigma-1-targeting multimodal compound HBK-15 reverses memory deficits and restores hippocampal plasticity under NMDA hypofunction
Sałaciak et al., Neurotherapeutics, 2025
This study investigated HBK-15, a multimodal compound with high affinity and agonist activity at sigma-1 receptors, in models of cognitive impairment associated with NMDA receptor hypofunction. HBK-15 reversed recognition and spatial memory deficits in mice, while its effects were linked to sigma-1 receptor activity. At the mechanistic level, the compound restored hippocampal long-term potentiation and improved disrupted theta–gamma coupling, providing evidence that S1R-targeting strategies can support hippocampal plasticity at both synaptic and network levels.
Together, these publications highlight the breadth of sigma-1 receptor research represented within the SIGMA-1EUROPE community in 2025. From the design of new ligands and imaging tools to studies of cellular signaling, experimental models, pain, and cognition, they illustrate the many perspectives from which S1R biology and its therapeutic potential are currently being explored.
Explore these and other publications in the SIGMA-1EUROPE Archives.
