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.
Comparable studies
Other experimental studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. | 2002 | Experimental study | |
| Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and... | 2004 | Experimental study | |
| Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Animal model | 2014 | Experimental study | |
| Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. | 2005 | Experimental study | |
| Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Rat brain striatum homogenates | 2009 | Laboratory experiment |
Citations in the library
Cited by 11
- Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A. MedChemComm December 1, 2011
- Semisynthetic neoclerodanes as kappa opioid receptor probes. Bioorganic & Medicinal Chemistry May 1, 2012
- Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor. European journal of medicinal chemistry October 6, 2014
- Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands. Bioorganic & Medicinal Chemistry Letters May 15, 2013
- Neoclerodanes as atypical opioid receptor ligands. Journal of Medicinal Chemistry May 9, 2013
and 6 more in the library
Cites 18
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae) Journal of the Chemical Society Perkin Transactions 1 1982
- Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum The Journal of Organic Chemistry November 1, 1984
- Ethnopharmacology of ska María Pastora (Salvia divinorum, Epling and Játiva-M.). Journal of Ethnopharmacology May 1, 1983
- Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice. Journal of Pharmacology and Experimental Therapeutics August 1, 2006
and 13 more in the library