| Salvinorin A is a neoclerodane diterpene isolated from Salvia divinorum, a mint plant native to Oaxaca, Mexico, that has been used by indigenous peoples in their divination rituals as well as to treat stomach problems. Salvinorin A was found to be a potent and selective agonist for the kappa opioid receptor. Modification of the C-2 acetate group of salvinorin A by a benzoate results in a compound with affinity and selectivity for the mu opioid receptor termed herkinorin. Herkinorin represents the first non-nitrogenous mu opioid receptor agonist discovered. The synthesis of a series of analogues based on herkinorin was undertaken to gain insight as to the structure activity relationship for the affinity and selectivity shown by herkinorin for the mu opioid receptor. Additional studies investigated the unique molecular biological and pharmacological characteristics of herkinorin and analogues.;Herkinorin was shown to activate the mu opioid receptor without recruitment of beta-arrestin 2 and also without causing internalization of the receptor from cell surface in vitro. Using a rodent model of nociception, herkinorin was shown to be active in vivo. More importantly, because of the unique way in which herkinorin activates the mu opioid receptor, it does not produce tolerance over a 5 day period and it remains active in animals that have become tolerant to the antinociceptive effects of morphine. The possibility of developing an analgesic that would not develop tolerance is attractive because it would allow for the alleviation of chronic pain without escalation of dose and would potentially have a lower abuse potential than standard opioids. |
