Article: A Route to Potent, Selective, and Biased Salvinorin Chemical Space.
ACS central science
2023 Volume 9, Issue 8, Page(s) 1567–1574
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 ... ...
| 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. |
|---|---|
| Language | English |
| Publishing date | 2023-07-12 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2374-7943 |
| ISSN | 2374-7943 |
| DOI | 10.1021/acscentsci.3c00616 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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