Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands

Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry wa...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-04, Vol.108 (17), p.6727-6732
Main Authors: Frankowski, Kevin J., Setola, Vincent, Evans, Jon M., Neuenswander, Ben, Roth, Bryan L., Aubé, Jeffrey, Schreiber, Stuart L.
Format: Article
Language:English
Subjects:
Alkaloids
Alkaloids - chemical synthesis
Alkaloids - chemistry
Alkaloids - pharmacology
Amines
Animals
Antitussive Agents - chemical synthesis
Antitussive Agents - chemistry
Antitussive Agents - pharmacology
Antitussives
Cell Line
Chemical compounds
Chemicals
Flowers & plants
Functional groups
Humans
Libraries
Ligands
Molecular Structure
Molecules
Nitrogen
Physical Sciences
Receptors
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Scaffolds
Stemonaceae - chemistry
T cell receptors
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Summary:Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1016558108