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A Route to Potent, Selective, and Biased Salvinorin Chemical Space
[Image: see text] 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 selec...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450872/ https://www.ncbi.nlm.nih.gov/pubmed/37637743 http://dx.doi.org/10.1021/acscentsci.3c00616 |
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author | Hill, Sarah J. Dao, Nathan Dang, Vuong Q. Stahl, Edward L. Bohn, Laura M. Shenvi, Ryan A. |
author_facet | Hill, Sarah J. Dao, Nathan Dang, Vuong Q. Stahl, Edward L. Bohn, Laura M. Shenvi, Ryan A. |
author_sort | Hill, Sarah J. |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-10450872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-104508722023-08-26 A Route to Potent, Selective, and Biased Salvinorin Chemical Space Hill, Sarah J. Dao, Nathan Dang, Vuong Q. Stahl, Edward L. Bohn, Laura M. Shenvi, Ryan A. ACS Cent Sci [Image: see text] 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. American Chemical Society 2023-07-12 /pmc/articles/PMC10450872/ /pubmed/37637743 http://dx.doi.org/10.1021/acscentsci.3c00616 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Hill, Sarah J. Dao, Nathan Dang, Vuong Q. Stahl, Edward L. Bohn, Laura M. Shenvi, Ryan A. A Route to Potent, Selective, and Biased Salvinorin Chemical Space |
title | A Route to Potent,
Selective, and Biased Salvinorin
Chemical Space |
title_full | A Route to Potent,
Selective, and Biased Salvinorin
Chemical Space |
title_fullStr | A Route to Potent,
Selective, and Biased Salvinorin
Chemical Space |
title_full_unstemmed | A Route to Potent,
Selective, and Biased Salvinorin
Chemical Space |
title_short | A Route to Potent,
Selective, and Biased Salvinorin
Chemical Space |
title_sort | route to potent,
selective, and biased salvinorin
chemical space |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450872/ https://www.ncbi.nlm.nih.gov/pubmed/37637743 http://dx.doi.org/10.1021/acscentsci.3c00616 |
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