Synthetic studies of neoclerodane diterpenoids from Salvia splendens and evaluation of opioid receptor affinity

doi:10.1016/j.tet.2008.08.043

Tetrahedron

Volume 64, Issue 43, 20 October 2008, Pages 10041-10048

https://doi.org/10.1016/j.tet.2008.08.043 Get rights and content

Abstract

Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific κ-opioid agonist. Several structural congeners of 1 isolated from Salvia splendens (2–8) together with a series of semisynthetic derivatives (9–24), some of which possess a pyrazoline structural moiety (9, 19–22), have been tested for affinity at human μ, δ, and κ opioid receptors. None of these compounds showed high affinity binding to these receptors. However, 10 showed modest affinity for κ receptors suggesting that other natural neoclerodanes from different Salvia species may possess opioid affinity.

Graphical abstract

Introduction

Salvinorin A (1), one of the neoclerodane diterpenes of Salvia divinorum Epling & Játiva (Labiatae), is a highly unusual drug that exerts its hallucinogenic effects as a potent and selective agonist of the κ-opioid receptor.¹ In the past few years, intensive research on the pharmacology and chemical transformations of salvinorin A have been made,1, 2, 3, 4, 5, 6 and its biosynthetic pathway has been elucidated⁷ and its asymmetric total synthesis has been achieved.⁸

Recently,⁹ some of us have reinvestigated the diterpene constituents of Salvia splendens Sellow ex Roem. & Schult isolating four new neoclerodanes (salvisplendins A–D, 4, 6, 7, and 8, respectively) together with the artifact 9, that results from 8 by treatment of the crude extract with diazomethane,⁹ and salviarin (2),¹⁰ splendidin (3),¹¹ and splenolides A and B (5),¹² all of them previously reported as constituents of this species.9, 10, 11, 12, 13

Taking into account the structural similarity between salvinorin A (1) and the diterpenes found in S. splendens (2–9), we decided to test these substances and two of their available derivatives (10 and 11)⁹ in order to explore whether such compounds may be useful as neuropharmacological agents.

Moreover, we have now obtained several new semisynthetic derivatives (12–24) starting from the more abundant constituents of S. splendens (2, 3, 5, 7, and 9),9, 13 and these compounds were also assayed as potential agonists at the opioid receptors. Three clerodanes of S. splendens, salviarin (2), splendidin (3), and splenolide B (5), have recently been tested for affinity at opioid receptors and none of these diterpenes showed significant binding to any of the opioid receptor subtypes.¹⁴ This work, however, demonstrates the potential utility of evaluating other neoclerodanes for their interaction with opioid receptors.

Section snippets

Results and discussion

As reported previously,¹ salvinorin A (1) with the natural (β) configuration at C-8 shows higher affinity and efficacy at the κ-opioid receptor. Hence, our first objective was to epimerize the C-8 asymmetric center of salviarin, splendidin, and splenolide B (2, 3, and 5, respectively). Treatment of 2 with K₂CO₃ in MeOH yielded 8-epi-salviarin (12) (Scheme 1), a derivative, which had been obtained by Rodríguez-Hahn and co-workers using similar reaction conditions.¹⁵ The complete assignment of

Conclusion

The data collected in this work indicate that the previous structure–activity relationships (SAR) may not be applicable to these neoclerodanes of general structure 9. They also suggest that these two series are not binding in an identical manner and that the orientation of the furan ring is a key interaction in the mode of binding of neoclerodane diterpenes at opioid receptors.

General

Melting points were determined on a Kofler block and are uncorrected. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter. IR spectra were obtained on a Perkin–Elmer Spectrum One spectrophotometer. ¹H and ¹³C NMR spectra were recorded in CDCl₃ solution, except for 13 and 15 (methanol-d₄), on a Varian INOVA 400 spectrometer at 400 and 100 MHz, respectively. Chemical shifts are reported in the δ scale and are referenced to residual CHCl₃ (δ 7.25) or methanol-d₄ (δ 3.30) signals for

Acknowledgements

This work was supported in part by funds from the Spanish ‘Comisión Interministerial de Ciencia y Tecnología’ (CICYT), grant No. CTQ2006-15279-C02-02, Italian ‘Università degli Studi di Palermo’, grant ‘Ex 60%-2005’, and R01DA018151 (to T.E.P.) from the National Institute on Drug Abuse. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

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Synthetic studies of neoclerodane diterpenoids from Salvia splendens and evaluation of opioid receptor affinity

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

Acknowledgements

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Phytochemistry

Phytochemistry

Phytochemistry

Phytochemistry

J. Med. Chem.

J. Med. Chem.

J. Am. Chem. Soc.

J. Nat. Prod.