Revised structure of deacetyl-1,10-didehydrosalvinorin G

In comparison with the NMR data of salvinorin A and its 8-epimer, the published structure of deacetyl-1,10-didehydrosalvinorin G was revised to its 8-epimer. The stereochemistry of 8-epi-deacetyl-1,10-didehydrosalvinorin G was further confirmed by NOESY and chemical synthesis.     

Autoxidation of salvinorin A under basic conditions

[reaction: see text] Treatment of salvinorin A (1a) with KOH in MeOH gave the enedione 3, for which the dienone structure 7 was recently proposed. Also isolated, after methylation, were the secotriesters 4a-c. A mechanism for this unusual series of autoxidations is proposed. Surprisingly, 4a showed weak affinity at the kappa-opioid receptor. Divinatorins A-C (2a-c) showed no affinity at opioid receptors. Attempted reduction of 3 to a novel salvinorin diol (9d) was unsuccessful, but careful deacetylation of salvinorin C (9a) provided a viable route to this compound. A general method for identifying salvinorin 8-epimers by TLC is also presented.     

Short synthesis of a novel class of salvinorin A analogs with hemiacetalic structure

Novel semisynthetic analogs of salvinorin A, a full agonist having extraordinary affinity as well as selectivity for the κ-opioid receptor (KOR), were obtained in good yields. The derivatives are remarkable for their unusual and unique hemiacetal structure in the salvinorin series of compounds. The formation of the hemiacetal occurs with epimerization at C-12, thus preserving the original configuration of salvinorin A. The dimethyl ester derivative of the hemiacetal was found to have an affinity for both KOR and MOR (μ-opioid receptor).     

Novel neoclerodane diterpene derivatives from the smoke of salvinorin A

Salvinorin A is a naturally occurring potent and selective kappa opioid receptor agonist, and smoking salvinorin A produces the most intense hallucinogenic effects in human. Eight neoclerodane diterpene derivatives were isolated from the smoke of salvinorin A, and their structures were identified by spectroscopic methods. The major structural changes include epimerizations, eliminations, and rearrangements.     

Unambiguous NMR spectral assignments of salvinorin A

The complete assignments of the (1)H and (13)C NMR spectra of the hallucinogenic neoclerodane diterpenoid salvinorin A were determined in three different NMR solvents using HSQC, HMBC and COSY. Solvent systems are described that allow the resolution of all (1)H signals. Virtual coupling was observed for the protons at C-2, C-3 and C-4 in the 600 MHz (1)H spectrum in CDCl(3). The complete assignments of the (1)H and (13)C NMR spectra of salvinorin B are also reported.     

Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A

Total synthesis of salvinorin A (1), a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective kappa-opioid agonist, was completed in 20 steps starting from enantiomerically pure hydroxy-Wieland-Miescher ketone 5.     

Intramolecular Diels-Alder/Tsuji allylation assembly of the functionalized trans-decalin of salvinorin A

An enantioselective synthesis of the highly functionalized trans-decalin core (2) of salvinorin A is described. The tetraene 4 was synthesized in six steps from a known L-(+)-tartaric acid derivative. Three contiguous stereocenters, two of them quaternary, on the trans-decalin were established asymmetrically by an intramolecular Diels-Alder/Tsuji allylation sequence.     

Second-generation synthesis of salvinorin A

Functionalization toward total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A was accomplished via three double sequences: bis-enol triflate synthesis, palladium-catalyzed double carbonylation to the bis-enol triflate, and samarium diiodide-mediated double conjugate reduction. The configuration at C-12 was controlled by chelation-controlled diastereoselective reduction.     

Direct analysis of Salvia divinorum leaves for salvinorin A by thin layer chromatography and desorption electrospray ionization multi‐stage tandem mass spectrometry

Salvia divinorum is widely cultivated in the US, Mexico, Central and South America and Europe and is consumed for its ability to produce hallucinogenic effects similar to those of other scheduled hallucinogenic drugs, such as LSD. Salvinorin A (SA), a kappa opiod receptor agonist and psychoactive constituent, is found primarily in the leaves and to a lesser extent in the stems of the plant. Herein, the analysis of intact S. divinorum leaves for SA and of acetone extracts separated using thin layer chromatography (TLC) is demonstrated using desorption electrospray ionization (DESI) mass spectrometry. The detection of SA using DESI in the positive ion mode is characterized by several ions associated with the compound – [M+H]⁺, [M+NH₄]⁺, [M+Na]⁺, [2M+NH₄]⁺, and [2M+Na]⁺. Confirmation of the identity of these ions is provided through exact mass measurements using a time‐of‐flight (ToF) mass spectrometer. The presence of SA in the leaves was confirmed by multi‐stage tandem mass spectrometry (MSⁿ) of the [M+H]⁺ ion using a linear ion trap mass spectrometer. Direct analysis of the leaves revealed several species of salvinorin in addition to SA as confirmed by MSⁿ, including salvinorin B, C, D/E, and divinatorin B. Further, the results from DESI imaging of a TLC separation of a commercial leaf extract and an acetone extract of S. divinorum leaves were in concordance with the TLC/DESI‐MS results of an authentic salvinorin A standard. The present study provides an example of both the direct analysis of intact plant materials for screening illicit substances and the coupling of TLC and DESI‐MS as a simple method for the examination of natural products. Copyright © 2010 John Wiley & Sons, Ltd.     

Thermal degradation products derived from the smoke of Salvia divinorum leaves

Smoking of Salvia divinorum leaves is the most common method for its psychotropic effects. Eleven thermal degradation products, including a new neoclerodane diterpene derivative, were isolated from the smoke of S. divinorum leaves, and their structures were identified by spectroscopic methods. The isolated compounds were evaluated for their binding affinities at the opioid receptors, and salvinorin A is still the most potent kappa opioid receptor agonist.     

Salvinicins A and B, new neoclerodane diterpenes from Salvia divinorum

[reaction: see text] Two new neoclerodane diterpenes, salvinicins A (4) and B (5), were isolated from the dried leaves of Salvia divinorum. The structures of these compounds were elucidated by spectroscopic techniques, including (1)H and (13)C NMR, NOESY, HMQC, and HMBC. The absolute stereochemistry of these compounds was assigned on the basis of single-crystal X-ray crystallographic analysis of salvinicin A (4) and a 3,4-dichlorobenzoate derivative of salvinorin B.     

A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A,a selective kappa opioid receptor agonist

Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based “agonist-bound” hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental pK _i values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

A Protecting-Group-Free Synthesis of (−)-Salvinorin A

A concise enantioselective total synthesis of the neoclerodane diterpene (−)-salvinorin A is reported. The stereogenic center at C-12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels-Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2-diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)-salvinorin A was synthesized in only 16 steps starting from 3-furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels-Alder strategy employing a 2-bromo-1,3-diene moiety was investigated.     

Forensic analysis of <Emphasis Type="Italic">Salvia divinorum</Emphasis> using multivariate statistical procedures. Part II: association of adulterated samples to <Emphasis Type="Italic">S. divinorum</Emphasis>

Salvia divinorum is a plant material that is of forensic interest due to the hallucinogenic nature of the active ingredient, salvinorin A. In this study, S. divinorum was extracted and spiked onto four different plant materials (S. divinorum, Salvia officinalis, Cannabis sativa, and Nicotiana tabacum) to simulate an adulterated sample that might be encountered in a forensic laboratory. The adulterated samples were extracted and analyzed by gas chromatography–mass spectrometry, and the resulting total ion chromatograms were subjected to a series of pretreatment procedures that were used to minimize non-chemical sources of variance in the data set. The data were then analyzed using principal components analysis (PCA) to investigate association of the adulterated extracts to unadulterated S. divinorum. While association was possible based on visual assessment of the PCA scores plot, additional procedures including Euclidean distance measurement, hierarchical cluster analysis, Student’s t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores to provide a statistical evaluation of the association observed. The advantages and limitations of each statistical procedure in a forensic context were compared and are presented herein.     

Massively parallel screening of the receptorome

The National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) is a resource that provides free screening of novel compounds to academic investigators. This program differs from other public-sector screening programs in that compounds are screened against a large panel of transmembrane receptors, channels, and transporters, a selection that currently includes a large portion of the whole neuro-receptorome. This review discusses the research areas that can profit from this resource, exemplified by recent findings. The first area is the identification of side effects of medications. Examples include the identification of the histamine H(1) receptor as being responsible for weight gain under antipsychotic treatment and the association of 5 HT(2B) receptor agonism with cardiac valvulopathy, which led to the removal of several medications. A second area is the identification of mechanisms of actions of medications and natural products. Examples are the finding that the kappa opioid receptor is the pharmacological target of the potent hallucinogen salvinorin A, that ephedrine and related compounds are not acting through direct sympathomimetic action, the identification of a strong dopaminergic action of WAY 100635, a compound that had been used as a selective 5 HT(1A) antagonist, and the discovery that the metabolite desmethylclozapine activates M(1) muscarinic receptors, an activity that might contribute to the clinical efficacy of the antipsychotic drug clozapine. A third, relatively new area is the identification of inert compounds as agonists for engineered designer receptors that no longer respond to their natural ligand (DREADDs) but exhibit unchanged signaling properties.     

Forensic analysis of <Emphasis Type="Italic">Salvia divinorum</Emphasis> using multivariate statistical procedures. Part I: discrimination from related <Emphasis Type="Italic">Salvia</Emphasis> species

Salvia divinorum is a hallucinogenic herb that is internationally regulated. In this study, salvinorin A, the active compound in S. divinorum, was extracted from S. divinorum plant leaves using a 5-min extraction with dichloromethane. Four additional Salvia species (Salvia officinalis, Salvia guaranitica, Salvia splendens, and Salvia nemorosa) were extracted using this procedure, and all extracts were analyzed by gas chromatography–mass spectrometry. Differentiation of S. divinorum from other Salvia species was successful based on visual assessment of the resulting chromatograms. To provide a more objective comparison, the total ion chromatograms (TICs) were subjected to principal components analysis (PCA). Prior to PCA, the TICs were subjected to a series of data pretreatment procedures to minimize non-chemical sources of variance in the data set. Successful discrimination of S. divinorum from the other four Salvia species was possible based on visual assessment of the PCA scores plot. To provide a numerical assessment of the discrimination, a series of statistical procedures such as Euclidean distance measurement, hierarchical cluster analysis, Student’s t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores. The statistical procedures were then compared to determine the advantages and disadvantages for forensic applications.     

Allosteric modulation model of the mu opioid receptor by herkinorin,a potent not alkaloidal agonist

Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information. Our herkinorin D-ICM-1 binding model predicted a binding free energy of ?11.52?±?1.14 kcal mol^?1 by alchemical free energy estimations, which is close to the experimental values ?10.91?±?0.2 and ?10.80?±?0.05 kcal mol^?1 and is in agreement with experimental structural information. Specifically, D-ICM-1 molecular dynamics simulations showed a water-mediated interaction between D-ICM-1 and the amino acid H297^6.52, this interaction coincides with the co-crystallized ligands. Another relevant interaction, with N127^2.63, allowed to rationalize herkinorin’s selectivity to mu over delta opioid receptors. Our suggested binding model for herkinorin is in agreement with this and additional experimental data. The most remarkable observation derived from our D-ICM-1 model is that herkinorin reaches an allosteric sodium ion binding site near N150^3.35. Key interactions in that region appear relevant for the lack of β-arrestin recruitment by herkinorin. This interaction is key for downstream signaling pathways involved in the development of side effects, such as tolerance. Future SAR studies and medicinal chemistry efforts will benefit from the structural information presented in this work.     

偶氮型光致变色液晶树状大分子的量子产率、异构转化率和活化能研究

研究了化合物端基含36个己氧基偶氮苯介晶基元的二代(G2)光致变色液晶树状大分子在氯仿及四氢呋喃溶液中的量子产率、吸收光强Ia、活化能E、异构转化率A/A0、热回复异构化速率常数kH及其反/顺异构体组分比A′/A′0,并与一代光致变色液晶碳硅烷树状大分子(G1)及介晶基元化合物(M3)的光化学行为进行了比较.在氯仿及四氢呋喃溶液中的量子产率的顺序均为M3>G1>G2,吸收光强Ia在氯仿及四氢呋喃溶液中的顺序分别为G2>G1>M3(氯仿)和M3>G1>G2(四氢呋喃),在氯仿及四氢呋喃溶液中活化能的顺序均为M3>G2>G1,在氯仿及四氢呋喃溶液中热回复异构化速率常数kH的顺序均为G1>G2>M3,在热回复异构化反应中的反/顺异构体组分比A′/A0′在氯仿及四氢呋喃溶液中的顺序均为G2>G1>M3.     

Tris(2‐aminoethyl)amine‐based ferrocene‐terminated dendrimers as burning rate catalysts for ammonium perchlorate‐based propellant decomposition

Ferrocene‐based derivatives show potential application as burning rate catalysts (BRCs) for solid composite propellants. However, migration problems of simple ferrocene‐based derivatives limit their application as BRCs in solid composite propellants. To overcome the migration problems of ferrocene‐based BRCs and to enhance the burning rate of ammonium perchlorate (AP)‐based propellants, zero‐ to second‐generation tris(2‐aminoethyl)amine‐based ferrocene‐terminated dendrimers (G0, G1 and G2) were synthesized. The structures of G0, G1 and G2 were confirmed using ¹H NMR, Fourier transform infrared and UV–visible spectroscopies. The electrochemical behavior of G0, G1 and G2 was investigated using cyclic voltammetry. It was found that G0, G1 and G2 showed redox behavior due to the presence of ferrocene and this redox behavior was diffusion controlled over the investigated scan range. The burning rate catalytic effect of G0, G1 and G2 on thermal decomposition of AP was investigated using thermogravimetry and differential thermogravimetry. G0, G1 and G2 showed good catalytic effect on the thermal decomposition of AP. Anti‐migration studies showed that migration of G0, G1 and G2 was much slower than that of 2,2‐bis(ethylferrocenyl)propane (catocene) and ferrocene.     

Conformations of dimethylhydrogen phosphonate (DMHP): a matrix isolation infrared and ab initio study

The infrared spectra of dimethylhydrogen phosphonate (DMHP) isolated in nitrogen, argon and krypton matrices using an effusive source at 298 and 373 K have been recorded. Experiments were also performed using a supersonic jet source to look for conformational cooling in the expansion process. As a result of these experiments, infrared spectral characteristics of the ground and higher energy conformers of the DMHP have been identified for the first time. The structures of DMHP were optimized at the hybrid B3LYP and Hartree fock (HF) levels of theory using the 6-31++G** basis sets. Computationally, four minima were obtained corresponding to DMHP conformers with G (+/-)G (-/+), G (-)G (-), TG (+) and TG (-) structures in the order of increasing energy. Frequency calculations were done to confirm that the structures were indeed minima on the potential energy surface (PES). The computed frequencies corroborated well with the experimental matrix isolation infrared frequencies leading to definite assignments of the infrared features of DMHP, for the G (+/-)G (-/+) and TG (+) conformers. At B3LYP/6-31++G** level, the energy difference between the G (+/-)G (-/+) and G (-)G (-) conformer was 1.53 kcal/mol, and that between G (+/-)G (-/+) and TG (+), G (+/-)G (-/+) and TG (-) were 1.65 and 1.95 kcal/mol. Transition-state calculations were also carried out at B3LYP/6-31++G** level connecting the G (+/-)G (-/+) to G (-)G (-), TG (+) and TG (-) conformers. Computations indicated that the conformer interconversion between G (-)G (-) --> G (+/-)G (-/+) is barrierless, whereas the barriers for TG (+) --> G (+/-)G (-/+) and TG (-) --> G (+/-)G (-/+) are 1.47 and 0.88 kcal/mol, respectively.