- N-skatyltryptamines-dual 5-ht6r/d2r ligands with antipsychotic and procognitive potential
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A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
- Bojarski, Andrzej J.,Bugno, Ryszard,Cie?lik, Paulina,Duszyńska, Beata,Handzlik, Jadwiga,Hogendorf, Adam S.,Hogendorf, Agata,Kaczorowska, Katarzyna,Kurczab, Rafa?,Latacz, Gniewomir,Lenda, Tomasz,Sata?a, Grzegorz,Staroń, Jakub,Szewczyk, Bernadeta
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- Asymmetric Dearomatizing Fluoroamidation of Indole Derivatives with Dianionic Phase-Transfer Catalyst
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Asymmetric dearomatizing fluorocyclization of indole derivatives was investigated using a dicarboxylate phase-transfer catalyst. This reaction proceeds under mild reaction conditions to provide fluoropyrroloindoline derivatives in a highly enantioselective manner. Various substitution patterns on the indole ring are well tolerated. To facilitate the reaction and ensure reproducibility, the addition of water is essential, and its possible role is discussed.
- Egami, Hiromichi,Hotta, Ryo,Otsubo, Minami,Rouno, Taiki,Niwa, Tomoki,Yamashita, Kenji,Hamashima, Yoshitaka
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supporting information
p. 5656 - 5660
(2020/07/14)
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- Tryptamine Synthesis by Iron Porphyrin Catalyzed C?H Functionalization of Indoles with Diazoacetonitrile
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The functionalization of C?H bonds with non-precious metal catalysts is an important research area for the development of efficient and sustainable processes. Herein, we describe the development of iron porphyrin catalyzed reactions of diazoacetonitrile with N-heterocycles yielding important precursors of tryptamines, along with experimental mechanistic studies and proof-of-concept studies of an enzymatic process with YfeX enzyme. By using readily available FeTPPCl, we achieved the highly efficient C?H functionalization of indole and indazole heterocycles. These transformations feature mild reaction conditions, excellent yields with broad functional group tolerance, can be conducted on gram scale, and thus provide a unique streamlined access to tryptamines.
- Hock, Katharina J.,Knorrscheidt, Anja,Hommelsheim, Renè,Ho, Junming,Weissenborn, Martin J.,Koenigs, Rene M.
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supporting information
p. 3630 - 3634
(2019/02/13)
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- Synthesis of indolyl-3-acetonitrile derivatives and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells
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Arvelexin is one of major constituents of Brassica rapa that exerts anti-inflammatory activities. Several indolyl-3-acetonitrile derivatives were synthesized as arvelexin analogs and evaluated for their abilities to inhibit NO and PGE2 productions in LPS-induced RAW 264.7 cells. Of the indolyl-3-acetonitriles synthesized, compound 2k, which possesses a hydroxyl group at C-7 position of the indole ring and an N-methyl substituent, more potently inhibited NO and PGE2 productions and was less cytotoxic than arvelexin on macrophage cells.
- Kwon, Tae Hoon,Yoon, Ik Hwan,Shin, Ji-Sun,Lee, Young Hun,Kwon, Bong Jin,Lee, Kyung-Tae,Lee, Yong Sup
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p. 2571 - 2574
(2013/07/04)
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- The discovery of carboline analogs as potent MAPKAP-K2 inhibitors
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The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-lo
- Wu, Jiang-Ping,Wang, Ji,Abeywardane, Asitha,Andersen, Denise,Emmanuel, Michel,Gautschi, Elda,Goldberg, Daniel R.,Kashem, Mohammed A.,Lukas, Susan,Mao, Wang,Martin, Leslie,Morwick, Tina,Moss, Neil,Pargellis, Christopher,Patel, Usha R.,Patnaude, Lori,Peet, Gregory W.,Skow, Donna,Snow, Roger J.,Ward, Yancey,Werneburg, Brian,White, Andre
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p. 4664 - 4669
(2008/02/13)
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- Mapping the melatonin receptor. 7. Subtype selective ligands based on β-substituted N-acyl-5-methoxytryptamines and β-Substituted N-acyl-5-methoxy-1-methyltryptamines
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A series of β-substituted and β,β-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT1 and MT2 receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores, β-Methylmelatonin (17a) and β,β-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus, N-Butanoyl 5-methoxy-1-methyl-β,β-trimethylenetryptamine (12c) is an antagonist at human MT1 receptors but an agonist at MT2, while N-butanoyl 5-methoxy-1-methyl-β,β-tetramethylenetryptamine (13c) is an antagonist at MT1 but had no action at MT2 and is one of the first examples of an MT1 selective antagonist.
- Tsotinis, Andrew,Vlachou, Margarita,Papahatjis, Demetris P.,Calogeropoulou, Theodora,Nikas, Spyros P.,Garratt, Peter J.,Piccio, Vincent,Vonhoff, Stefan,Davidson, Kathryn,Teh, Muy-Teck,Sugden, David
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p. 3509 - 3519
(2007/10/03)
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- Synthesis of 3-Amino-2-(3-indolyl)propanol and propanoate derivatives and preliminary cardiovascular evaluation in rats
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A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties. The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate ant
- Perez-Alvarez, Victor,Morales-Rios, Martha S.,Hong, Enrique,Joseph-Nathan, Pedro
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p. 246 - 252
(2007/10/03)
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- Compounds effective in the treatment of circadian rhythms and related disorders, the novel pharmaceutical preparations and novel method of application
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The novel compounds of formula: STR1 in which R is isopropyl, cyclohexyl, phenyl, CH 3, Br or I; or H R 1 is CH 3 or cyclopropyl and R 2 is H or Br, and when R 1 is cyclopropyl and R 2 is H, R is other than H, and when R 1 is CH 3 and R 2 is H, R is other than H, and when R 1 is CH 3 and R 2 is H, R is other than I, and when R is CH 3 and R 2 is H, R 1 is other than CH 3, and when R is phenyl and R 2 is H, R 1 is other than CH 3, exhibit superior activity in the treatment of pathologies which interfere with the circadian rhythm. A novel method of preparation is described according to which the pharmaceutical compositions containing the novel compounds, as well as compounds already known, are administered transdermally. The novel method of administration results in sustained peripheral blood level. Novel pharmaceutical compositions are described suitable for transdermal administration.
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