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Pharmacology & Chemistry

Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

May 11, 2017 / Neuroscience, Papers, Pharmacology & Chemistry, Salvia / Salvinorin A / By / , , , , , ,

Abstract

Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.
Sherwood, A. M., Crowley, R. S., Paton, K. F., Biggerstaff, A., Neuenswander, B., Day, V. W., … & Prisinzano, T. E. (2017). Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability. Journal of Medicinal Chemistry, 60(9), 3866-3878. 10.1021/acs.jmedchem.7b00148
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Psychotria viridis: Chemical constituents from leaves and biological properties

April 1, 2017 / Ayahuasca, Biology & Ethnobotany, Papers, Pharmacology & Chemistry, Publications / By / , , , , , ,

Abstract

The phytochemical study of hexane, chloroform and methanol extracts from leaves of Psychotria viridis resulted in the identification of: the pentacyclic triterpenes, ursolic and oleanolic acid; the steroids, 24-methylene-cycloartanol, stigmasterol and β-sitosterol; the glycosylated steroids 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol; a polyunsaturated triterpene, squalene; the esters of glycerol, 1-palmitoylglycerol and triacylglycerol; a mixture of long chain hydrocarbons; the aldehyde nonacosanal; the long chain fat acids hentriacontanoic, hexadecanoic and heptadenoic acid; the ester methyl heptadecanoate; the 4-methyl-epi-quinate and two indole alkaloids, N,N-dimethyltryptamine (DMT) and N-methyltryptamine. The chemical structures were determined by means of spectroscopic (IR, 1H and 13C NMR, HSQC, HMBC and NOESY) and spectrometric (CG-MS and LCMS-ESI-ITTOF) methods. The study of biologic properties of P. viridis consisted in the evaluation of the acetylcholinesterase inhibition and cytotoxic activities. The hexane, chloroform, ethyl acetate and methanol extracts, the substances 24-methylene-cycloartanol, DMT and a mixture of 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol showed cholinesterase inhibiting activity. This activity induced by chloroform and ethyl acetate extracts was higher than 90%. The methanol and ethyl acetate extracts inhibit the growth and/or induce the death of the tumor cells strains B16F10 and 4T1, without damaging the integrity of the normal cells BHK and CHO. DMT also demonstrated a marked activity against tumor cell strains B16F10 and 4T1.
SOARES, D., DUARTE, L. P., CAVALCANTI, A. D., SILVA, F. C., BRAGA, A. D., LOPES, M. T., … & VIEIRA-FILHO, S. A. (2017). Psychotria viridis: Chemical constituents from leaves and biological properties. Anais da Academia Brasileira de Ciências, 89(2), 927-938. 10.1590/0001-3765201720160411
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Synthesis of New Harmine Isoxazoles and Evaluation of their Potential Anti-Alzheimer, Anti-inflammatory, and Anticancer Activities

March 1, 2017 / Ayahuasca, Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , ,

Abstract

Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by (1)H NMR, (13)C NMR and HRMS. The evaluation of their anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3 ± 1.9% at 100 µM). Compound 2 exhibited the best anti-AChE activity (IC50=1.9 ± 1.5 µM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC50=5.0 ± 0.3 µM (3a) and IC50=6.3 ± 0.4 µM (3b) against HCT 116 cells, IC50=5.0 ± 1.0 µM (3d) against MCF7 cells).

Filali, I., Romdhane, A., Znati, M., B Jannet, H., & Bouajila, J. (2016). Synthesis of New Harmine Isoxazoles and Evaluation of their Potential Anti-Alzheimer, Anti-inflammatory, and Anticancer Activities. Medicinal Chemistry, 12(2), 184-190. 10.2174/157340641202160209104115
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LSD instead of 25I-NBOMe: The revival of LSD? A case report

February 27, 2017 / LSD, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Observation: We report a case of a 25-year-old man crushed by a train while he was returning from a rave party. The consumption of 25I-NBOMe was rapidly evoked by people who had participated at the party.

Materials and methods: In this context, the post-mortem toxicological expertise was completed by a broad screening using high-resolution mass spectrometry detection (LC-HRMS). Three hundred NPS and metabolites (including 25B, 25C and 25I-NBOMes) can be found with this method. A targeted screening in MRM mode was also performed on a smaller number of hallucinogens.

Results: The toxicological analyses were performed on blood and urine samples. Amphetamines, cocaine, cannabinoids and opiates were not detected. Ethanol was measured at 0.71 g/L and 1.59 g/L in blood and urine samples, respectively. The screening by LC-HRMS did not reveal the presence of NPS, including NBOMes. The targeted screening in MRM mode revealed the presence of LSD and its metabolite, the 2-oxo-3-hydroxy-LSD. LSD was quantified at 0.2 ng/mL in blood.

Conclusion: This case alerts on the frequent confusion between NBOMes and LSD and on the renewed interest for LSD due to the popularity of NBOMes. This case therefore encourages the prudence and research of all hallucinogenic substances, even when the context is evocative.

Bodeau, S., Bennis, Y., Régnaut, O., Fabresse, N., Richeval, C., Humbert, L., … & Lemaire-Hurtel, A. S. (2017). LSD instead of 25I-NBOMe: The revival of LSD? A case report. Toxicologie Analytique et Clinique, 29(1), 139-143. 10.1016/j.toxac.2016.12.007
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Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance

January 31, 2017 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / By /

Abstract

Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.

Dinis-Oliveira, R. J. (2016). METABOLISM OF PSILOCYBIN AND PSILOCIN: CLINICAL AND FORENSIC TOXICOLOGICAL RELEVANCE. Drug Metabolism Reviews, (just-accepted), 1-21. 10.1080/03602532.2016.1278228
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Determination of Tryptamines and β-Carbolines in Ayahuasca Beverage Consumed During Brazilian Religious Ceremonies

January 19, 2017 / Ayahuasca, Biology & Ethnobotany, Papers, Pharmacology & Chemistry, Publications / By / , ,

Abstract:

Ayahuasca is a potent hallucinogenic beverage prepared from Banisteriopsis caapi in combination with other psychoactive plants. N,N-dimethyltryptamine, tryptamine, harmine, harmaline, harmalol, and tetrahydroharmine were quantified in ayahuasca samples using a simple and low-cost method based on SPE and LC with UV diode-array detection. The experimental variables that affect the SPE method, such as type of solid phase and nature of solvent, were optimized. The method showed good linearity (r > 0.9902) and repeatability (RSD < 0.8%) for alkaloid compounds, with an LOD of 0.12 mg/L. The proposed method was used to analyze 20 samples from an ayahuasca cooking process from a religious group located in the municipality of Fortaleza, state of Ceará, Brazil. The results showed that concentrations of the target compounds ranged from 0.3 to 36.7 g/L for these samples.

Santos, M. C., Navickiene, S., & Gaujac, A. (2017). Determination of Tryptamines and β-Carbolines in Ayahuasca Beverage Consumed During Brazilian Religious Ceremonies. Journal of AOAC International. 10.5740/jaoacint.16-0337
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The Iboga Alkaloids

January 1, 2017 / Iboga / Ibogaine, Papers, Pharmacology & Chemistry, Publications / By / ,

Abstract

Iboga alkaloids are a particular class of indolomonoterpenes most often characterized by an isoquinuclidine nucleus. Their first occurrence was detected in the roots of Tabernanthe iboga, a sacred plant to the people of Gabon, which made it cult object. Ibogaine is the main representative of this class of alkaloids and its psychoactive properties are well documented. It has been proposed as a drug cessation treatment and has a wide range of activities in targeting opioids, cocaine, and alcohol. The purpose of this chapter is to provide a background on this molecule and related compounds and to update knowledge on the most recent advances made. Difficulties linked to the status of ibogaine as a drug in several countries have hampered its development, but 18-methoxycoronaridine is currently under evaluation for the same purposes and for the treatment of leishmaniasis. The chapter is divided into six parts: an introduction aiming at defining what is called an iboga alkaloid, and this is followed by current knowledge on their biosynthesis, which unfortunately remains a “black box” as far as the key construction step is concerned. Many of these alkaloids are still being discovered and the third and fourth parts of the chapter discuss the analytical tools in use for this purpose and give lists of new monomeric and dimeric alkaloids belonging to this class. When necessary, the structures are discussed especially with regard to absolute configuration determinations, which remain a point of weakness in their assignments. Part V gives an account of progress made in the synthesis, partial and total, which the authors believe is key to providing solid solutions to the industrial development of the most promising molecules. The last part of the chapter is devoted to the biological properties of iboga alkaloids, with particular emphasis on ibogaine and 18-methoxycoronaridine.

Lavaud, C., & Massiot, G. (2017). The Iboga Alkaloids. In Progress in the Chemistry of Organic Natural Products 105 (pp. 89-136). Springer International Publishing. 10.1007/978-3-319-49712-9_2
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Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase

November 19, 2016 / Neuroscience, Papers, Pharmacology & Chemistry, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , , , , , ,

Abstract

Salvia divinorum commonly known as diviner’s sage, is an ethnomedicinal plant of the mint family (Lamiaceae). S. divinorum is rich in clerodane-type diterpenoids, which accumulate predominantly in leaf glandular trichomes. The main bioactive metabolite, salvinorin A, is the first non-nitrogenous natural compound known to function as an opioid-receptor agonist, and is undergoing clinical trials for potential use in treating neuropsychiatric diseases and drug addictions. We report here the discovery and functional characterization of two S. divinorumditerpene synthases (diTPSs), the ent-copalyl diphosphate (ent-CPP) synthase SdCPS1, and the clerodienyl diphosphate (CLPP) synthase SdCPS2. Mining of leaf- and trichome-specific transcriptomes revealed five diTPSs, two of which are class II diTPSs (SdCPS1-2) and three are class I enzymes (SdKSL1-3). Of the class II diTPSs, transient expression in Nicotiana benthamianaidentified SdCPS1 as an ent-CPP synthase, which is prevalent in roots and, together with SdKSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with NMR analysis identified SdCPS2 as a CLPP synthase. A role of SdCPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II diTPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of SdCPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II diTPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts.

Pelot, K. A., Mitchell, R., Kwon, M., Hagelthorn, D. M., Wardman, J. F., Chiang, A., … & Zerbe, P. (2016). Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase. The Plant Journal. 10.1111/tpj.13427
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Ibogan, Tacaman, and Cytotoxic Bisindole Alkaloids from Tabernaemontana. Cononusine, an Iboga Alkaloid with Unusual Incorporation of a Pyrrolidone Moiety

April 28, 2015 / Iboga / Ibogaine, Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , , ,

Abstract

Abstract Image

Six new indole alkaloids, viz., cononusine (1, a rare example of an iboga–pyrrolidone conjugate), ervaluteine (2), vincamajicine (3), tacamonidine (4), 6-oxoibogaine (5), and N4-chloromethylnorfluorocurarine chloride (6), and two new vobasinyl-iboga bisindole alkaloids, ervatensines A (7) and B (8), in addition to other known alkaloids, were isolated from the stem-bark extract of the Malayan Tabernaemontana corymbosa. The structures of these alkaloids were established on the basis of NMR and MS analyses and, in one instance (7), confirmed by X-ray diffraction analysis. Vincamajicine (3) showed appreciable activity in reversing multidrug resistance in vincristine-resistant KB cells (IC50 2.62 μM), while ervatensines A (7) and B (8) and two other known bisindoles displayed pronounced in vitro growth inhibitory activity against human KB cells (IC50 < 2 μM). Compounds 7 and 8 also showed good growth inhibitory activity against A549, MCF-7, MDA-468, HCT-116, and HT-29 cells (IC50 0.70–4.19 μM). Cell cycle and annexin V-FITC apoptosis assays indicated that compounds 7 and 8 inhibited proliferation of HCT-116 and MDA-468 cells, evoking apoptotic and necrotic cell death.

Lim, K. H., Raja, V. J., Bradshaw, T. D., Lim, S. H., Low, Y. Y., & Kam, T. S. (2015). Ibogan, Tacaman, and Cytotoxic Bisindole Alkaloids from Tabernaemontana. Cononusine, an Iboga Alkaloid with Unusual Incorporation of a Pyrrolidone Moiety. Journal of natural products. http://dx.doi.org/10.1021/acs.jnatprod.5b00117

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Fatty acid constituents of Peganum harmala plant using Gas Chromatography–Mass Spectroscopy

April 25, 2015 / Papers, Pharmacology & Chemistry, Publications / By / ,

Abstract

Fatty acid contents of the Peganum harmala plant as a result of hexane extraction were analyzed using GC–MS. The saturated fatty acid composition of the harmal plant was tetradecanoic, pentadecanoic, tridecanoic, hexadecanoic, heptadecanoic and octadecanoic acids, while the saturated fatty acid derivatives were 12-methyl tetradecanoic, 5,9,13-trimethyl tetradecanoic and 2-methyl octadecanoic acids. The most abundant fatty acid was hexadecanoic with concentration 48.13% followed by octadecanoic with concentration 13.80%. There are four unsaturated fatty acids called (E)-9-dodecenoic, (Z)-9-hexadecenoic, (Z,Z)-9,12-octadecadienoic and (Z,Z,Z)-9,12,15-octadecatrienoic. The most abundant unsaturated fatty acid was (Z,Z,Z)-9,12,15-octadecatrienoic with concentration 14.79% followed by (Z,Z)-9,12-octadecadienoic with concentration 10.61%. Also, there are eight non-fatty acid compounds 1-octadecene, 6,10,14-trimethyl-2-pentadecanone, (E)-15-heptadecenal, oxacyclohexadecan-2 one, 1,2,2,6,8-pentamethyl-7-oxabicyclo[4.3.1]dec-8-en-10-one, hexadecane-1,2-diol, n-heneicosane and eicosan-3-ol.

Moussa, T. A., & Almaghrabi, O. A. (2015). Fatty acid constituents of Peganum harmala plant using Gas Chromatography–Mass Spectroscopy. Saudi Journal of Biological Sciences. https://dx.doi.org/10.1016/j.sjbs.2015.04.013
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