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Interest in sigma-1 receptors (S1Rs) has significantly increased in the last 25 years and more recently for their role in pain modulation. S1Rs are novel chaperone proteins that modulate several cellular processes and can modulate the activity of many ion channels and receptors. They are heavily localized in pain pathways, leading to the development of S1R antagonists for pain modulation. Although the exact mechanism by which S1R antagonists act is unclear, there has been marked advances in the preclinical and clinical development of S1R antagonists. This review covers the brief history of S1Rs and the research leading to the development of S1R antagonists in clinical trials for chronic pain. Focus is given to E-52862 and [ 18 F]FTC-146 (aka CM-304) as their clinical development has broken ground for S1R antagonists- with both being first-in-class ligands for treatment and diagnostic imaging, respectively. S1R antagonists represent a unique intracellular target for pain modulation, due to the receptor’s chaperone activity in modulating various proteins in pain pathways. The research on S1R has grown exponentially in the last 20 years, and as more is understood about the basic science of the receptor, the drug development in this field will also flourish.

Advances with the discovery and development of novel sigma 1 receptor antagonists for the management of pain