- Synthesis and Functional Characterization of 2-(2,5-Dimethoxyphenyl)-N-(2-fluorobenzyl)ethanamine (25H-NBF) Positional Isomers
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Serotonergic psychedelics, substances exerting their pharmacological action through activation of the serotonin 2A receptor (5-HT2AR), have continuously comprised a substantial fraction of the over 1000 reported New Psychoactive Substances (NPS) so far. Within this category, N-benzyl derived phenethylamines, such as NBOMes and NBFs, have shown to be of particular relevance. As these substances remain incompletely characterized, this study aimed at synthesizing positional isomers of 25H-NBF, with two methoxy groups placed on different positions of the phenyl group of the phenethylamine moiety. These isomers were then functionally characterized in an in vitro bioassay monitoring the recruitment of β-Arrestin 2 to the 5-HT2AR through luminescent readout via the NanoBiT technology. The obtained results provide insight into the optimal substitution pattern of the phenyl group of the phenethylamine moiety of N-benzyl derived substances, a feature so far mostly explored in the phenethylamines underived at the N-position. In the employed bioassay, the most potent substances were 24H-NBF (EC50 value of 158 nM), 26H-NBF (397 nM), and 25H-NBF (448 nM), with 23H-NBF, 35H-NBF, and 34H-NBF yielding μM EC50 values. A similar ranking was obtained for the compounds' efficacy: Taking as a reference LSD (lysergic acid diethylamide), 24H-, 26H-, and 25H-NBF had an efficacy of 106-107%, followed by 23H-NBF (96.1%), 34H-NBF (75.2%), and 35H-NBF (58.9%). The stronger activity of 24H-, 25H-, and 26H-NBF emphasizes the important role of the methoxy group at position 2 of the phenethylamine moiety for the in vitro functionality of NBF substances.
- Pottie, Eline,Kupriyanova, Olga V.,Shevyrin, Vadim A.,Stove, Christophe P.
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p. 1667 - 1673
(2021/05/31)
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- Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
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A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.
- Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
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p. 346 - 364
(2019/01/08)
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- Biomimetic Phosphate-Catalyzed Pictet-Spengler Reaction for the Synthesis of 1,1′-Disubstituted and Spiro-Tetrahydroisoquinoline Alkaloids
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Tetrahydroisoquinoline (THIQ) alkaloids are an important group of compounds that exhibit a range of bioactivities. Here, a phosphate buffer-catalyzed Pictet-Spengler reaction (PSR) using unreactive ketone substrates is described. A variety of 1,1′-disubst
- Zhao, Jianxiong,Méndez-Sánchez, Daniel,Ward, John M.,Hailes, Helen C.
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p. 7702 - 7710
(2019/06/17)
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- Cobalt-based nanoparticles prepared from MOF-carbon templates as efficient hydrogenation catalysts
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The development of efficient and selective nanostructured catalysts for industrially relevant hydrogenation reactions continues to be an actual goal of chemical research. In particular, the hydrogenation of nitriles and nitroarenes is of importance for the production of primary amines, which constitute essential feedstocks and key intermediates for advanced chemicals, life science molecules and materials. Herein, we report the preparation of graphene shell encapsulated Co3O4- and Co-nanoparticles supported on carbon by the template synthesis of cobalt-terephthalic acid MOF on carbon and subsequent pyrolysis. The resulting nanoparticles create stable and reusable catalysts for selective hydrogenation of functionalized and structurally diverse aromatic, heterocyclic and aliphatic nitriles, and as well as nitro compounds to primary amines (>65 examples). The synthetic and practical utility of this novel non-noble metal-based hydrogenation protocol is demonstrated by upscaling several reactions to multigram-scale and recycling of the catalyst.
- Murugesan, Kathiravan,Senthamarai, Thirusangumurugan,Sohail, Manzar,Alshammari, Ahmad S.,Pohl, Marga-Martina,Beller, Matthias,Jagadeesh, Rajenahally V.
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p. 8553 - 8560
(2018/11/30)
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- Synthesis of 3-Benzazepines by Metal-Free Oxidative C–H Bond Functionalization–Ring Expansion Tandem Reaction
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A metal-free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C–H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven-ring N-heterocyclic structures under mild conditions using a 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3-benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations. (Figure presented.).
- Gini, Andrea,Bamberger, Julia,Luis-Barrera, Javier,Zurro, Mercedes,Mas-Ballesté, Rubén,Alemán, José,Manche?o, Olga García
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supporting information
p. 4049 - 4056
(2016/12/30)
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- Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability
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Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.
- Kinney, William A.,McDonnell, Mark E.,Zhong, Hua Marlon,Liu, Chaomin,Yang, Lanyi,Ling, Wei,Qian, Tao,Chen, Yu,Cai, Zhijie,Petkanas, Dean,Brenneman, Douglas E.
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supporting information
p. 424 - 428
(2016/05/19)
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