1. Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists.
- Author
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Mostinski Y, Noy G, Kumar R, Tsvelikhovsky D, and Priel A
- Subjects
- Animals, Avian Proteins agonists, Avian Proteins metabolism, Calcium metabolism, Cells, Cultured, Chickens, HEK293 Cells, Humans, Lactones chemistry, Membrane Potentials drug effects, Membrane Potentials physiology, Neurons drug effects, Neurons metabolism, Neurotransmitter Agents chemistry, Patch-Clamp Techniques, Protein Domains, Rats, Spiro Compounds chemistry, TRPV Cation Channels metabolism, Trigeminal Ganglion drug effects, Trigeminal Ganglion metabolism, Lactones pharmacology, Neurotransmitter Agents pharmacology, Spiro Compounds pharmacology, TRPV Cation Channels agonists
- Abstract
TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system. Here, we establish the existence of a unique family of synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.
- Published
- 2017
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