- Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids
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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.
- Dahlén, Johan,Konradsson, Peter,Liu, Huiling,Rexander, Anders,Vestling, Erik,Wallgren, Jakob,Wu, Xiongyu
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supporting information
p. 517 - 520
(2020/03/13)
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- Indol-3-ylcycloalkyl ketones: Effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity
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Several 3-acylindoles with high affinity for the CB2 cannabinoid receptor and selectivity over the CB1 receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB2 agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB2 receptor.Astudy of N1 nonaromatic side chain variants provided potent agonists at the CB2 receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB2 receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB2 receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB2 functional assay than were nonaromatic side chain analogues.
- Frost, Jennifer M.,Dart, Michael J.,Tietje, Karin R.,Garrison, Tiffany R.,Grayson, George K.,Daza, Anthony V.,El-Kouhen, Odile F.,Yao, Betty B.,Hsieh, Gin C.,Pai, Madhavi,Zhu, Chang Z.,Chandran, Prasant,Meyer, Michael D.
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p. 295 - 315
(2010/06/11)
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- In vitro and in vivo characterization of A-796260: A selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models
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Background and purpose: Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are μ-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist. Experimental approach: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and μ-opioid receptor antagonists. Key results: A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or μ-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain.
- Yao,Hsieh,Frost,Fan,Garrison,Daza,Grayson,Zhu,Pai,Chandran,Salyers,Wensink,Honore,Sullivan,Dart,Meyer
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p. 390 - 401
(2008/09/17)
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- Indol-3-yl-tetramethylcyclopropyl ketones: Effects of indole ring substitution on CB2 cannabinoid receptor activity
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A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB2 cannabinoid receptor ligands. Two unsubstituted indoles (5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB2 and CB1 binding affinities and activity in a CB2 in vitro functional assay. Indole ring substitutions had varying effects on CB2 and CB1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB2/CB1 binding selectivity in some cases (i.e., 7-9,15-20). All indoles with the morpholino-ethyl side chain (32-43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs (5-31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia (32, 15).
- Frost, Jennifer M.,Dart, Michael J.,Tietje, Karin R.,Garrison, Tiffany R.,Grayson, George K.,Daza, Anthony V.,El-Kouhen, Odile F.,Miller, Loan N.,Li, Lanlan,Yao, Betty B.,Hsieh, Gin C.,Pai, Madhavi,Zhu, Chang Z.,Chandran, Prasant,Meyer, Michael D.
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p. 1904 - 1912
(2008/09/21)
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- 3-CYCLOALKYLCARBONYL INDOLES AS CANNABINOID RECEPTOR LIGANDS
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The present invention provides novel compounds of Formula (I), which are CB2 selective ligands useful for the treatment of pain.
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Page/Page column 32
(2008/06/13)
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