- Indole derivatives and its application on the medicament
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The invention provides indole derivatives or stereisomers, tautomers, nitrogen oxides, solvate, metabolic products, pharmaceutically acceptable salts or prodrugs thereof for treating the alzheimer disease. The invention further discloses a pharmaceutical composition containing the compounds and a method of using the compounds or the pharmaceutical composition thereof to treat the alzheimer disease.
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Paragraph 0381; 0391-0394
(2019/03/28)
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- Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation
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Molecular modeling and structure-activity relationship studies were performed to propose a model for binding of the neurotransmitter serotonin (5-HT) to the human serotonin transporter (hSERT). Homology models were constructed using the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, as the template and three slightly different sequence alignments. Induced fit docking of 5-HT into hSERT homology models resulted in two different binding modes. Both show a salt bridge between Asp98 and the charged primary amine of 5-HT, and both have the 5-HT C6 position of the indole ring pointing toward Ala173. The difference between the two orientations of 5-HT is an enantiofacial discrimination of the indole ring, resulting in the 5-hydroxyl group of 5-HT being vicinal to either Ser438/Thr439 or Ala169/Ile172/Ala173. To assess the binding experimentally, binding affinities for 5-HT and 17 analogues toward wild type and 13 single point mutants of hSERT were measured using an approach termed paired mutant-ligand analogue complementation (PaMLAC). The proposed ligand-protein interaction was systematically examined by disrupting it through site-directed mutagenesis and reestablishing another interaction via a ligand analogue matching the mutated residue, thereby minimizing the risk of identifying indirect effects. The interactions between Asp98 and the primary amine of 5-HT and the interaction between the C6-position of 5-HT and hSERT position 173 was confirmed using PaMLAC. The measured binding affinities of various mutants and 5-HT analogues allowed for a distinction between the two proposed binding modes of 5-HT and biochemically support the model for 5-HT binding in hSERT where the 5-hydroxyl group is in close proximity to Thr439.
- Celik, Leyla,Sinning, Steffen,Severinsen, Kasper,Hansen, Carsten G.,Moller, Maria S.,Bols, Mikael,Wiborg, Ove,Schiott, Birgit
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p. 3853 - 3865
(2008/12/20)
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- Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)
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A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be poten
- Schmitz, William D.,Denhart, Derek J.,Brenner, Allison B.,Ditta, Jonathan L.,Mattson, Ronald J.,Mattson, Gail K.,Molski, Thaddeus F.,Macor, John E.
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p. 1619 - 1621
(2007/10/03)
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- Design and synthesis of aminopropyl tetrahydroindole-based indolin-2-ones as selective and potent inhibitors of Src and Yes tyrosine kinase
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A novel series of substituted 3-[3-(aminopropyl)-4,5,6,7-tetrahydro-1H- indol-2-ylmethylene]-1,3-dihydro-indole-2-ones was discovered as potent inhibitors of the non-receptor tyrosine kinase Src and Yes. A structure-activity relationship was developed in order to optimize their potency and selectivity. Syntheses of these compounds are also described herein.
- Guan, Huiping,Laird, A. Douglas,Blake, Robert A.,Tang, Cho,Liang, Chris
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p. 187 - 190
(2007/10/03)
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- One-pot synthesis of homotryptamines from indoles
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A method is presented for the one-pot synthesis of homotryptamines by the MacMillan reaction of indoles with acrolein followed by reductive amination.
- Denhart, Derek J.,Mattson, Ronald J.,Ditta, Jonathan L.,Macor, John E.
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p. 3803 - 3805
(2007/10/03)
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