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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Natural compounds Furan-containing natural products Phytochemistry Medicinal chemistry Pharmacology Drug discovery Structure-activity relationships sar Kappa opioid receptors Receptor agonists Chemical synthesis Microwave-assisted synthesis Novel methods Chemical modification Organic synthesis Methodology |
| Citations | 40 |
| Key findings | 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.