Salvaging Salvinorin: From Hallucinogen to Potential Therapeutic through Chemical Synthesis

Salvinorin A (SalA), the most potent naturally occurring hallucinogen, is a polycyclic terpenoid from Salvia divinorum that acts as a selective kappa-opioid receptor (KOR) agonist, a target for non-addictive analgesics. Its complex structure limits synthetic modifications. In this work, Shenvi, Bohn, and co-workers developed a concise synthetic route to SalA analogues that overcome the natural compound's liabilities, yielding compounds with improved activity, KOR-selectivity, and functional bias. This approach offers new opportunities for exploring KOR-selective compounds, which avoid the addictive effects associated with mu-opioid receptor activation, potentially addressing the societal burden of opioid abuse.

Study at a glance

Abstract

Natural products have served as rich sources of therapeutics dating back to the earliest human civilizations in the form of traditional medicines and more recently as single molecule therapies for a range of diseases. Their diverse biological activities stem from their often complex structures, which can endow natural products with desirable properties relative to synthetic molecules found in typical pharmaceutical libraries. These same intricate structures can, however, limit chemists’ ability to prepare these compounds de novo�a process termed total synthesis�or restrict derivatives available for biochemical exploration to simple peripheral changes to the natural compound of interest�termed semisynthesis. One such bioactive natural product that challenges the state of the art in organic synthesis is the polycyclic terpenoid salvinorin A (SalA, Figure 1). SalA is the main psychoactive principle of Salvia divinorum, a plant used in traditional Mazatec religion to facilitate visionary states, with SalA itself classified as the most potent naturally occurring hallucinogen ever discovered. SalA derives its bioactivity from potent and selective agonism of the kappa-opioid receptor (KOR), a target of interest for the development of next-generation analgesics. In this issue of ACS Central Science, Shenvi, Bohn, and co-workers showcase a concise and flexible synthetic approach to analogues of SalA that circumvent many of the liabilities associated with the natural compound, while exceeding it in terms of activity, KOR-selectivity, and functional bias. Traditionally, naturally occurring alkaloids such as morphine have taken center stage among clinically relevant analgesics. Such compounds also interact with opioid receptors�in the case of morphine, most strongly with the mu-opioid receptor (MOR)�to exert their function. Given that receptor selectivity can play a crucial role in the observation of adverse side effects�most poignantly, a high propensity for addiction, contributing to the significant societal burden arising from opioid abuse�it is desirable to find new opioid receptor agonists. KOR-selective compounds, in particular, hold promise as activation of this receptor is not noted to produce addictive effects. In this respect, SalA, which interestingly lacks the basic amine characteristic of KOR agonists, may offer new opportunities to explore different binding interactions through its oxygenated terpene scaffold.