Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.
Journal of natural products – April 25, 2011
Source: PubMed
Summary
Understanding how natural compounds like salvinorin A interact with the body is crucial. Researchers developed a novel microwave-assisted method to precisely modify this potent natural product. They successfully created unique forms that act as full agonists at kappa opioid receptors, revealing new insights into their structure-activity relationships. This innovative approach rapidly probes how furan-containing natural products function.
Abstract
As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.