Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A

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.

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

“…Thus, 4a was dissolved in DMSO-d 6 , the 1 H NMR spectrum was recorded (Figure 2b), and then two equivalents of cysteamine were added and the spectrum recorded after 5 min (Figure 2c). This spectrum showed the disappearance of the olefinic protons of the acrylate moiety.…”

“…It gained significant scientific interest as the only non-nitrogenous KOR agonist with no apparent structural similarity to other ligands. This has encouraged several research groups to study the structure-activity relationships of 1, and a plethora of salvinorin A derivatives has been synthesized over the past decade [3][4][5][6][7][8]. Some of these analogues exhibit interesting pharmacological profiles from full KOR agonist to partial DOR or MOR agonist and antagonists.…”

Microwaves in the Synthesis of Natural Products

“…The main active component of S. divinorum has been identified as the neoclerodane diterpene salvinorin A (303). Prisinzano and co-workers [64] reaction. Salvinorin A (303) was reacted with diethyl or dimethyl acetylenedicarboxylate under MW irradiation resulting in the formation of cycloadducts 304 in high yields.…”

Why Do Plants Contain Biologically Active Compounds?

“…As of the end of 2013, the semisynthesis of 233 salvinorin A analogs involving all functional groups in the molecule has been reported (Lovell et al 2010(Lovell et al , 2012Ma et al 2010;Cunningham et al 2011;Fichna et al 2011;Lozama et al 2011;Prevatt-Smith et al 2011;Polepally et al 2013). Out of this number 27 compounds had affinity (K i ) lower than 10 nM (Figure 4.2).…”