Since natural products are essentially chemical weapons that plants use for self-defence, it is not surprising that only a few weak vanilloid antagonists have been discovered in the natural products pool. These plant secondary metabolites include ginsenosides from ginseng , the flavonoid galangin  and the sesquiterpene lactone thapsigargin . These compounds are weak (mM level) TRPV1 inhibitors, and their affinity for TRPV1 is marginal compared to other targets (e.g. SERCAs for thapsigargin).
Several endogenous steroids can also bind and inhibit TRPV . For example, dehydroepiandrosterone (27a, DHEA), a major blood steroid, can reversibly inhibit capsaicin-induced currents in dorsal root ganglion neurons with an EC50 value 6.7 mM, which is close to the physiological concentration of this compound. Since DHEA levels climax in the mid-20s and then decrease with age, elderly people might be more sensitive to capsaicin than young adults. Even more interesting, distinct structure-activity relationships were discovered for steroids: for instance, 3-epiDHEA (27b) could potentiate, and not inhibit, capsaicin responses, raising the possibility that the steroid framework might provide an interesting platform for the discovery of new TRPV1 antagonists. At a molecular level, it is not clear if steroids are allosteric modulators of TRPV1 or if they bind directly to the capsaicin-binding domain of the receptor.
Another intriguing observation is that the female sex-hormone 17b-estradiol (28) could dramatically potentiate capsaicin responses, whereas the male hormone testosterone had marginal inhibitory activity. Sex differences in pain responses have long been known, with women being more sensitive to capsaicin-induced pain than men . The differential modulation of capsaicin responses by female and male hormones might provide a rationale to explain this observation.
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