Studies toward the Pharmacophore of Salvinorin A, a Potent κ Opioid Receptor Agonist

Abstract

Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity, but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.Salvinorin A (1) 1 was isolated from Salvia divinorum, a traditional medicine of the Mazatec Indians of Oaxaca, Mexico. Infusions of the leaves induce visions, and 1 is a potent hallucinogen in humans. 2 1 is a selective agonist at the κ opioid receptor (KOR), 3 with comparable potency and efficacy to the synthetic KOR agonists U50488 and U69593. 4 KOR ligands appear to have therapeutic potential against a range of conditions, including pain, 5 nausea, 6 depression, 7 and HIV infection. 8 1 is the only non-nitrogenous KOR agonist known, with no structural similarity to other such compounds. 3 Given this, 1 represents a valuable lead for the development of more potent and selective KOR ligands. At present, little is known of the compound's structure-activity relationships. The deacetyl compound salvinorin B (2), also isolated from S. divinorum ,9 is inactive at the KOR, while substitution of more hindered esters at the 2-position reduces or abolishes activity. 4 To probe the importance of other functional groups in 1, we set out to test related compounds from this plant, as well as semisynthetic derivatives of 1, for binding affinity and functional activity at cloned opioid receptors.Salvinorins A (1), D (4), and E (5) were isolated as described previously. 10 Acetylation of 4 gave salvinorin C (6). 11 The known 1α-hydroxy derivative 8 9,12a and diacetate 9 11 were prepared by published procedures (Figure 1).A number of new derivatives of 1 were also synthesized, and the structures verified by NMR analysis, including DEPT, COSY, HMQC, HMBC and nOe experiments. As a preliminary step, 1 itself was reexamined using these techniques. This confirmed the original 1 H and 13 C assignments (based on decoupling experiments) 9 in all cases except the overlapping multiplets of H-6 and H-7. The HMQC spectrum showed crosspeaks from C-6 (δ 38.1 ppm) to multiplets *Corresponding author. Tel: +61-3-8344-6488. Fax: +61-3-9347-5180. E-mail: masr@unimelb.edu.au.. Supporting Information Available: Experimental procedures, characterization data, 1 H and 13 C NMR spectra, and IUPAC/NIST Chemical Identifiers (INChIs) of the target compounds (the spectra of 4 and 5 were published previously). 10 This material is available free of charge via the Internet at http://pubs.acs.org. Until recently, no satisfactory procedure for deacetylation of 1 had been published. Brown reported that KCN in refluxing MeOH/THF gave 2 in quantitative yield, 13a but in our hands 8-epi-2 was the major product. Additionally, the epimers were not resolved on silica using Br...

Unambiguous NMR spectral assignments of salvinorin A

“…1 -4 In connection with our biosynthetic studies of this molecule, the complete assignment of its 1 H and 13 C NMR spectra was necessary. In order to resolve inconsistencies between the NMR spectral assignments found in the two original reports of this substance 5,6 and a later publication, 7 detailed NMR analysis was carried out using a 600-MHz instrument.…”

“…The 1 H and 13 C assignments of Valdes et al are in excellent agreement with our data, and differed significantly only at positions 6 and 7, where the signal of the 7ˇ-H was assigned to 6ˇ-H. 6 More recently published 1 H NMR data had the assignments of the 7˛and 7ˇH atoms reversed. 7 The NMR spectra of salvinorin B (2-desacetyl salvinorin A) were also assigned ( …”

neo-Clerodane diterpenoids from Salvia dugesii and their bioactive studies

“…Considering many neo-clerodane diterpenoids have been isolated from different Salvia species previously, along with the spectral features obseverd in the NMR spectra, 1 could be ascribed to be a neo-clerodane diterpenoid. [3][4][5][6][7][8]15 Carefully analysis of the NMR spectral data indicated that the 1D NMR data (Table 1) of 1 are very similar to those of salvileucalin A, a novel spirocyclic diterpenoid with a rearranged neo-clerodane keleton from Salvia leucantha. 15 The differences observed in the 1 H and 13 C NMR spectra were the presence of one methylene (δ C 23.5, C-2) and a methine (δ C 44.6, C-5) signals in 1 instead of the signals for the unsaturated methine at C-2 and the unsaturated quaternary carbon at C-5 in salvileucalin A.…”

“…The IR spectrum showed the presence of furan ring (1504 and 874 cm −1 ) and α,β-unsaturated γ-lactone moieties (1754 and 1682cm -1 ). [2][3][4][5][6][7][8] The 13 C NMR and DEPT spectra of 1 exhibited signals for 20 carbons, including two lactonic carbonyls, six quaternary carbons, six methines (including four unsaturated ones and an oxygenated one), and six methylenes (one unsaturated one and one oxygenated). Considering many neo-clerodane diterpenoids have been isolated from different Salvia species previously, along with the spectral features obseverd in the NMR spectra, 1 could be ascribed to be a neo-clerodane diterpenoid.…”

“…1 Clerodane diterpenoids, a type of characteristic secondary metabolites of Salvia species, have been reported frequently with diverse biological activities from different Salvia species distributed in Mexico and Central and South America. [2][3][4][5][6][7] Previously chemical studied on the title plant afforded several neo-clerodane diterpenoids. 8 With the aim of searching for useful metabolites from this invasive plant and continuing our systematic studies of Salvia species, [8][9][10] the chemical constituents of S. dugesii was investigated, and five new neo-clerodane diterpenoids (dugesins C-G, 1-5) were isolated together with six known ones: dugesins A and B, 8 tilifodiolide, 3 isosalvipuberulin, 4 salviandulin E, 5 and salvifaricin.…”