Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.
Anthony Lozama, Christopher W Cunningham, Michael J Caspers, Justin T Douglas, Christina M Dersch, Richard B Rothman, Thomas E Prisinzano
Journal of natural products April 25, 2011 DOI: 10.1021/np1007872 via PubMed
Summary
AI-generated from the abstractNew chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Natural compounds Furan-containing natural products Phytochemistry Medicinal chemistry |
| Citations | 40 |
| Key finding | Microwave-assisted Diels-Alder cycloaddition on salvinorin A's furan ring produced cycloadducts that, when retaining a bent oxanorbornadiene system, maintained kappa opioid receptor affinity and full agonist activity, while aromatization to a planar phenyl ring reduced affinity. |
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.