The active component of Salvia Divinorum is Salvinorin A a neoclerodane diterpenoid which is a potent and selective kappa-opioid receptor agonist. It is the only known non-nitrogen containing opioid receptor ligand with a unique mode of binding to the kappa-opioid receptor protein. There is growing evidence to suggest that nonpeptidic kappa-opioid receptor selective agonists could be a potential treatment for pain. Additionally, kappa-opioid receptor selective antagonists represent a potential treatment for cocaine addiction, depression and mania. Thus, Salvinorin A represents an exceptionally intriguing starting point to address these two pressing issues as well as to gain important structural information about the kappa-opioid receptor. To address these challenges we propose to complete the SAR of the effects of the stereochemistry of Salvinorin A on its agonist/partial agonist/ antagonist profile. The effects of three of the seven stereogenic centers of Salvinorin A with respect to affinity and potency at the k opioid receptor have been explored to date. The immediate objective is to establish the SAR of the remaining stereocenters of salvinorin A so that new synthetic kappa-opioid receptor selective agonist/partial agonist/antagonist profile scaffolds can be identified and provide novel probes for CNS opioid receptors. The long-term objective of this research is to use the scaffolds identified in this proposal as the starting poins for the discovery of new therapeutic agents to treat pain and substance abuse. To explore this theme we will pursue these two specific aims:
Specific Aim #1 : Synthesis of four stereoisomers of Salvinorin A and synthesis of three des-methyl (C5, C9 mono-des-methyl and di-des-methyl) analogs of Salvinorin A.
Specific Aim #2 : Test each of the stereoisomers for selectivity of binding to the three cloned human opioid receptors (mu, delta and kappa) and determine their agonist/antagonist profile in a functional assay. This study will compliment the current SAR knowledge of Salvinorin A and make a significant contribution to our understanding of the stereochemical requirements of the kappa-opioid receptor.