New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human κ opioid receptors

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Abstract

Bioactivity-guided fractionation of the leaves of Salvia divinorum has resulted in the isolation of three new neoclerodane diterpenoids: divinatorin D (1), divinatorin E (2), and salvinorin G (3), together with 10 known terpenoids, divinatorin C (4), hardwickiic acid (5), salvinorin-A (6), -B (7), -C (8), -D (9), -E (10), and -F (11), presqualene alcohol (12), and (E)-phytol (13). The structures of these three new compounds were characterized by spectroscopic methods. All these compounds were evaluated for their binding affinities to the human κ opioid receptors. In comparison with divinatorin D (1), divinatorin E (2), and salvinorin G (3), salvinorin A (6) is still the most potent κ agonist.

Graphical abstract

Three new neoclerodane diterpenoids—divinatorin D, divinatorin E, and salvinorin G, along with 10 known terpenoids, were isolated from the leaves of Salvia divinorum. All these compounds were evaluated for their binding affinities to the human κ opioid receptors.

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Introduction

The kappa (κ) opioid receptor (KOR) is one of three main types of opioid receptors. It is differentiated from mu (μ) and delta (δ) opioid receptors by distinct genes and proteins, tissue expression patterns, functional properties, and pharmacological profiles of selective agonists and antagonists.1 Activation of the KOR in vivo produces numerous effects, including analgesia, dysphoria, corticosteroid elevation, diuresis, antipruritic effect, immunomodulation, and decreases in pilocarpine-induced seizures and associated mossy fiber sprouting and hilar neuron loss.2 The KOR also participates in the expression of chronic morphine-induced withdrawal syndrome and mediates the aversive effects of Δ9-tetrahydrocannabinol.3, 4 The synthetic arylacetamides, U50,488H, U69,593, spiradoline, enadoline, ICI 204448, and asimadoline, are selective KOR agonists.5, 6 Interestingly, the KOR agonist U69,593 produces depressive-like effects, and the KOR antagonists norBNI and ANTI produce antidepressant-like effects in animal models.7, 8 Furthermore, KOR agonists appear to affect mood in humans.9, 10 In addition, several other compounds, such as TRK 820 and HZ2, were reported to be KOR agonists and may be useful as analgesics, water diuretics, and antipruritics.11, 12, 13, 14 Recently, salvinorin A was identified as a KOR agonist.15, 16, 17, 18, 19

As part of our ongoing investigation, we initiated a comprehensive fractionation study guided by KOR binding activity in an attempt to find new KOR agonists or antagonists from Salvia divinorum (Lamiaceae). S. divinorum is a traditional medicine of the Mazatec Indians of Oaxaca, Mexico.20 It has been used for many hundreds of years, primarily for its psychoactive (hallucinogenic) effects in their divination rites. An extract prepared from the crushed leaves induces ‘visions’ and the psychotropic effects, including effects on mood, have been verified by a number of researchers.21 Salvinorin A, a nonnitrogenous neoclerodane diterpenoid, was isolated and identified to be the key ingredient for these psychoactive effects.22 In addition, salvinorin A was confirmed to have very high affinity and selectivity for the KOR at nanomolar concentrations.15, 16, 17, 18, 19 Previous phytochemical investigations of this plant have resulted in the isolation of 15 terpenoids, including salvinorins A–F and divinatorins A–C.21, 23, 24, 25, 26 Herein, we report the isolation and characterization of three new diterpenoids (1, 2, and 3) and 10 known terpenoids (413), and their KOR binding activities.

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Results and discussion

The dried leaves (4.6 kg) of S. divinorum were sequentially extracted with hexane, acetone, and methanol. The acetone extract showed the most potent binding activity to human KOR; the hexane and methanol fractions were much less potent. Following published procedures,23, 24 the pigments in acetone extract were removed by chromatography on activated carbon. Upon further recrystallization from acetone and methanol, a significant amount of salvinorin A (∼10 g) was isolated. The supernatant of the

General experimental procedures

Optical rotations were measured with an AUTOPOL III digital polarimeter. NMR spectra were recorded on a Varian VXR300 spectrometer with TMS as the internal standard. EI-MS spectra were obtained on a HP5972 Series Mass spectrometer. ESI-TOFMS spectra were measured on a Micromass Plateform II mass spectrometer. Activated Carbon (Aldrich, USA), Celite 545 (Acros Organics, USA), and Silica Gel (Fisher Scientific, USA) were used for column chromatography. TLC was performed on precoated silica gel 60

Acknowledgments

The author thanks Drs. Puling Wang and Qing Liao, Department of Chemistry and Chemical Biology, Harvard University, for MS determination, Dr. Ruicao Shen for help with optical rotation measurements, and Dr. Cecile Beguin for procurement of the S. divinorum leaves.

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