AI Article Synopsis
- Salvinorins are potential next-generation drugs for pain relief, itch reduction, and hallucinogenic effects through their strong interaction with the kappa-opioid receptor, unlike typical opioids which have basic amines.
- The authors introduce a new method for synthesizing salvinorins using a specialized organocatalyst that allows for precise chemical reactions while overcoming previous limitations.
- This synthesis yields various salvinorin analogs that demonstrate improved effectiveness, selectivity, and stability compared to salvinorin A, highlighting their promise for pharmaceutical development.
Article Abstract
The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile/unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability, and functional bias of salvinorin A itself.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450872 | PMC |
| http://dx.doi.org/10.1021/acscentsci.3c00616 | DOI Listing |
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