scholarly journals Chain Substituted Cannabilactones with Selectivity for the CB2 Cannabinoid Receptor

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3559 ◽  
Author(s):  
Shakiru O. Alapafuja ◽  
Spyros P. Nikas ◽  
Thanh C. Ho ◽  
Fei Tong ◽  
Othman Benchama ◽  
...  
Keyword(s):  
First Generation ◽  
Cannabinoid Receptor ◽  
Species Difference ◽  
Synthetic Cannabinoids ◽  
Side Chain ◽  
Sar Studies ◽  
Selective Ligands ◽  
Carbon Substitution ◽  
Synthetic Intermediates ◽  
Cyano Groups

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1′-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain’s length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (Ki = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 3.7 ± 1.5 nM, E(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol.

scholarly journals Identification and Analytical Characterization of a Novel Synthetic Cannabinoid-Type Substance in Herbal Material in Europe

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 793
Author(s):  
Emmanouil D. Tsochatzis ◽  
Joao Alberto Lopes ◽  
Margaret V. Holland ◽  
Fabiano Reniero ◽  
Giovanni Palmieri ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cannabinoid Receptor ◽  
Analytical Data ◽  
Synthetic Cannabinoids ◽  
Synthetic Cannabinoid ◽  
Gas Chromatography Mass Spectrometry ◽  
New Psychoactive Substances ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
Analytical Laboratories

The rapid diffusion of new psychoactive substances (NPS) presents unprecedented challenges to both customs authorities and analytical laboratories involved in their detection and characterization. In this study an analytical approach to the identification and structural elucidation of a novel synthetic cannabimimetic, quinolin-8-yl-3-[(4,4-difluoropiperidin-1-yl) sulfonyl]-4-methylbenzoate (2F-QMPSB), detected in seized herbal material, is detailed. An acid precursor 4-methyl-3-(4,4-difluoro-1-piperidinylsulfonyl) benzoic acid (2F-MPSBA), has also been identified in the same seized material. After extraction from the herbal material the synthetic cannabimimetic, also referred to as synthetic cannabinoid receptor agonists or “synthetic cannabinoids”, was characterized using gas chromatography-mass spectrometry (GC-MS), 1H, 13C, 19F and 15N nuclear magnetic resonance (NMR) and high-resolution tandem mass spectrometry (HR-MS/MS) combined with chromatographic separation. A cheminformatics platform was used to manage and interpret the analytical data from these techniques.

scholarly journals Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders?

2020 ◽  
Vol 21 (12) ◽  
pp. 4221
Author(s):  
Tomasz Charytoniuk ◽  
Hubert Zywno ◽  
Karolina Konstantynowicz-Nowicka ◽  
Klaudia Berk ◽  
Wiktor Bzdega ◽  
...  
Keyword(s):  
Physical Activity ◽  
Neurodegenerative Disorders ◽  
Therapeutic Approach ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Antidepressant Effect ◽  
Brain Physiology ◽  
Current State ◽  
Neurological Effects

The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue. Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue. Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies. Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.

scholarly journals Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid

2018 ◽  
Vol 14 ◽  
pp. 2737-2744 ◽  
Author(s):  
Jacqueline Pollini ◽  
Valentina Bragoni ◽  
Lukas J Gooßen
Keyword(s):  
First Generation ◽  
Anacardic Acid ◽  
Side Chain ◽  
Tyrosinase Inhibitor ◽  
Target Compound ◽  
Selective Precipitation ◽  
Acid Component ◽  
Cross Metathesis ◽  
Cashew Nutshell Liquid ◽  
Bond Isomers

A convenient and sustainable three-step synthesis of the tyrosinase inhibitor 2-hydroxy-6-tridecylbenzoic acid was developed that starts directly from the anacardic acid component of natural cashew nutshell liquid (CNSL). Natural CNSL contains 60–70% of anacardic acid as a mixture of several double bond isomers. The anacardic acid component was converted into a uniform starting material by ethenolysis of the entire mixture and subsequent selective precipitation of 6-(ω-nonenyl)salicylic acid from cold pentane. The olefinic side chain of this intermediate was elongated by its cross-metathesis with 1-hexene using a first generation Hoveyda–Grubbs catalyst, which was reused as precatalyst in a subsequent hydrogenation step. Overall, the target compound was obtained in an overall yield of 61% based on the unsaturated anacardic acid content and 34% based on the crude CNSL.

scholarly journals Activity-Based Detection of Cannabinoids in Serum and Plasma Samples

2018 ◽  
Vol 64 (6) ◽  
pp. 918-926 ◽  
Author(s):  
Annelies Cannaert ◽  
Jolien Storme ◽  
Cornelius Hess ◽  
Volker Auwärter ◽  
Sarah M R Wille ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Activation ◽  
Synthetic Cannabinoid ◽  
New Psychoactive Substances ◽  
Simple Liquid ◽  
Analytical Sensitivity ◽  
Monitoring Centre ◽  
Screening Strategies

Abstract BACKGROUND Synthetic cannabinoids are the largest group of new psychoactive substances monitored by the European Monitoring Centre of Drugs and Drug Addiction. The rapid proliferation of novel analogs makes the detection of these new derivatives challenging and has initiated considerable interest in the development of so-called “untargeted” screening strategies to detect these compounds. METHODS We developed new, stable bioassays in which cannabinoid receptor activation by cannabinoids led to recruitment of truncated β-arrestin 2 (βarr2) to the cannabinoid receptors, resulting in functional complementation of a split luciferase, allowing readout via bioluminescence. Aliquots (500 μL) of authentic serum (n = 45) and plasma (n = 73) samples were used for simple liquid–liquid extraction with hexane:ethyl acetate (99:1 v/v). Following evaporation and reconstitution in 100 μL of Opti-MEM® I/methanol (50/50 v/v), 10 μL of these extracts was analyzed in the bioassays. RESULTS Truncation of βarr2 significantly (for both cannabinoid receptors; P = 0.0034 and 0.0427) improved the analytical sensitivity over the previously published bioassays applied on urine samples. The new bioassays detected cannabinoid receptor activation by authentic serum or plasma extracts, in which synthetic cannabinoids were present at low- or sub-nanogram per milliliter concentration or in which Δ9-tetrahydrocannabinol was present at concentrations >12 ng/mL. For synthetic cannabinoid detection, analytical sensitivity was 82%, with an analytical specificity of 100%. CONCLUSIONS The bioassays have the potential to serve as a first-line screening tool for (synthetic) cannabinoid activity in serum or plasma and may complement conventional analytical assays and/or precede analytical (mass spectrometry based) confirmation.

scholarly journals Cumyl‐CBMICA: A new synthetic cannabinoid receptor agonist containing a cyclobutyl methyl side chain

2020 ◽  
Author(s):  
Sebastian Halter ◽  
Benedikt Pulver ◽  
Maurice Wilde ◽  
Belal Haschimi ◽  
Folker Westphal ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Side Chain ◽  
Synthetic Cannabinoid Receptor Agonist

Synthesis of the 5-Fluoro-4-hydroxypentyl Side Chain Metabolites of Synthetic Cannabinoids 5F-APINACA and CUMYL-5F-PINACA

Synthesis ◽  
2018 ◽  
Vol 50 (23) ◽  
pp. 4683-4689 ◽  
Author(s):  
Mark Trudell ◽  
Ryan McKinnie ◽  
Tasneam Darweesh ◽  
Phoebe Zito ◽  
Terrell Shields
Keyword(s):  
Efficient Method ◽  
Synthetic Cannabinoids ◽  
Synthetic Cannabinoid ◽  
Protecting Groups ◽  
Side Chain ◽  
Hydroxy Metabolites

An efficient method for the construction of the 5-fluoro-4-hydroxypentyl side chain common to a number of synthetic cannabinoid metabolites was developed. A series of hydroxyl protecting groups was examined to assess the viability as orthogonal protecting groups for epoxidation and regioselective hydrofluorination. The 1-[5-fluoro-4-(diphenyl-tert-butylsilyloxy)]pentyl tosylate was prepared in 67% overall yield (six steps) from pent-4-en-1-ol and was employed for the synthesis of the 4-hydroxy metabolites of the synthetic cannabinoid 5F-APINACA and CUMYL-5F-PINACA.

Pharmacophoric Requirements for the Cannabinoid Side Chain. Probing the Cannabinoid Receptor Subsite at C1‘

2003 ◽  
Vol 46 (15) ◽  
pp. 3221-3229 ◽  
Author(s):  
Demetris P. Papahatjis ◽  
Spyros P. Nikas ◽  
Therapia Kourouli ◽  
Ravi Chari ◽  
Wei Xu ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Side Chain

Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1

2013 ◽  
Vol 87 (7) ◽  
pp. 1287-1297 ◽  
Author(s):  
Verena J. Koller ◽  
Gerhard J. Zlabinger ◽  
Volker Auwärter ◽  
Sabine Fuchs ◽  
Siegfried Knasmueller
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Subtype ◽  
Binding Affinities ◽  
High Binding

Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids

Synlett ◽  
2020 ◽  
Vol 31 (05) ◽  
pp. 517-520 ◽  
Author(s):  
Jakob Wallgren ◽  
Anders Rexander ◽  
Erik Vestling ◽  
Huiling Liu ◽  
Johan Dahlén ◽  
...  
Keyword(s):  
Synthetic Cannabinoids ◽  
Parent Drug ◽  
Cb1 Receptor ◽  
Reference Standards ◽  
Urinary Biomarkers ◽  
Drug Intake ◽  
Side Chain ◽  
Urinary Biomarker ◽  
Synthetic Route ◽  
Extensive Metabolism

Synthetic cannabinoids are a group of compounds that act on the CB1 receptor and are used illicitly as substitutes for cannabis. Given the rapid and extensive metabolism of synthetic cannabinoids, urinary biomarkers are essential if proof of drug intake is to be obtained in forensic laboratories. To identify good biomarker candidates, the metabolism of synthetic cannabinoids must be studied and reference standards need to be acquired. Studies on the metabolism of synthetic cannabinoids containing a terminally fluorinated pentyl side chain have shown that hydroxylation can occur at the four position of the side chain. This makes the 4-hydroxy-5-fluoropentyl side-chain metabolite a good urinary biomarker for proving intake of the corresponding parent drug, as this compound cannot be formed from its nonfluorinated analogue. Here, a concise synthetic route to the 4-hydroxy-5-fluoropentyl side-chain metabolites of the synthetic cannabinoids STS-135, MAM-2201, AM-2201, and XLR-11 is reported.

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