The sigma-1 receptor (σ1R) is an intriguing receptor molecule whose function remains unknown. For years, scientists have puzzled over the role of this receptor protein, which is expressed in nearly all mammalian cells. Despite its ubiquity, no natural ligand for σ1R has been clearly identified, apart from its modulation by endogenous dimethyltryptamine (DMT). In addition, this receptor has a complex pharmacology, since it is able to bind a plethora of structurally diverse drugs that possess different therapeutic and pharmacological profiles (e.g., neuroleptics, antidepressants, antitussives, drugs of abuse and drugs for the treatment of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease).
As a consequence of both its complex pharmacology and the lack of clear functional assays to identify and classify σ1R ligands, the potential use of these drugs as therapeutic agents is currently unrealistic. To tackle this problem we developed a novel methodology to predict the intrinsic analgesic nature of relevant σ1R-based molecules. Therefore, we engineered a σ1R biosensor based on an intramolecular FRET-based approach. Interestingly, by using this biosensor we were able to establish a close relationship between ligand-mediated σ1R conformational switch (i.e. intrinsic efficacy) and biological activity (i.e. analgesia) of σ1R-based compounds. Hence, we presented a new assay that enables the unbiased evaluation of the intrinsic nature of σ1R drugs, thus constituting a powerful pharmacological tool that will propel the pharmacotherapeutic use of σ1R-based molecules. Overall, this novel methodology may have a broad impact on the medicinal chemistry surrounding the σ1R pharmacology.
Additional reading:
Effects of the Dopamine Stabilizer, Pridopidine, on Basal and Phencyclidine-Induced Locomotion: Role of Dopamine D2 and Sigma-1 Receptors. (2018) Sahlholm, K., Valle-León, M., Taura, J., Fernández-Dueñas, V. & Ciruela, F. CNS & Neurological Disorders-Drug Targets 17 (7), 522 - 527..
Exploring drug-receptor interaction kinetics: Lessons from a sigma-1 receptor transmembrane biosensor. (2017) Fernández-Dueñas, V., Burgueño, J. & Ciruela, F. Frontiers in Pharmacology 8, 4.
Predicting the antinociceptive efficacy of sigma-1 receptor ligands by a novel receptor fluorescence resonance energy (FRET) based biosensor. (2014) Gómez-Soler, M., Fernández-Dueñas, V., Portillo-Salido, E., Pérez, P., Zamanillo, D., Vela, J.M., Burgueño, J. & Ciruela, F. Journal of Medicinal Chemistry 57 (1), 238-242.