Synthesis of Heterocyclic Analogues of Salvinorin A

The unique opioid salvinorin A is isolated from the known psychoactive plant Salvia divinorum. This plant is currently being sold on the internet as a legal hallucinogen. Salvinorin A has proved to be the first example of a non-nitorgenous ligand for opioid receptors. Salvinorin A, is a polyfunctional furan containing natural product with seven chiral centers. Furan rings in natural products are known to have the potential for hepatotoxicity. Our aim was to synthesize analogues of salvinorin A to further understand the role of the requirements for molecular recognition at opioid receptors. In additipon, we sought to decrease the risk of potential toxicity that is inherent with the furan ring. Compounds were chosen for their ability to act as bioisosteric replacements for the furan ring. Other heterocyclic groups were also added to introduce aromatic moieties at the C- 2 position, which has been shown to affect selectivity for opioid receptors. The methodology implemented to modify salvinorin A, allowed us to create analogues without affect the stereochemistry of the other chiral centers of salvinorin A. It is expected that novel agents based on salvinorin A will have potential to treat drug dependence and pain. The research is funded by a grant from the National Institute on Drug Abuse (DA18151)