Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM 3

Background and Purpose The melastatin‐related transient receptor potential TRPM 3 is a calcium‐permeable nonselective cation channel that can be activated by the neurosteroid pregnenolone sulphate ( PregS ) and heat. T RPM 3‐deficient mice show an impaired perception of noxious heat. Hence, drugs inhibiting TRPM 3 possibly get in focus of analgesic therapy. Experimental Approach Fluorometric methods were used to identify novel TRPM 3‐blocking compounds and to characterize their potency and selectivity to block TRPM 3 but not other sensory TRP channels. Biophysical properties of the block were assessed using electrophysiological methods. Single cell calcium measurements confirmed the block of endogenously expressed TRPM 3 channels in rat and mouse dorsal root ganglion ( DRG ) neurones. Key Results By screening a compound library, we identified three natural compounds as potent blockers of TRPM 3. Naringenin and hesperetin belong to the citrus fruit flavanones, and ononetin is a deoxybenzoin. Eriodictyol, a metabolite of naringenin and hesperetin, was still biologically active as a TRPM 3 blocker. The compounds exhibited a marked specificity for recombinant TRPM 3 and blocked PregS ‐induced [ C a 2+ ] i signals in freshly isolated DRG neurones. Conclusion and Implications The data indicate that citrus fruit flavonoids are potent and selective blockers of TRPM 3. Their potencies ranged from upper nanomolar to lower micromolar concentrations. Since physiological functions of TRPM 3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM 3 in vivo . Considering the involvement of TRPM 3 in nociception, TRPM 3 blockers may represent a novel concept for analgesic treatment.