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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...

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Autores principales: Hill, Sarah J., Dao, Nathan, Dang, Vuong Q., Stahl, Edward L., Bohn, Laura M., Shenvi, Ryan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
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.
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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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