- Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants
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Some novel 2-methyl-3-aminopropiophenones were synthesized and their centrally acting muscle relaxant activities were,evaluated for an inhibitory effect on the flexor reflex in rats. The structure-activity relationships are discussed. In this series 2-methyl-3-pyrrolidino-1-(4-trifluoromethylphenyl)-propan-1-one (28) showed significant centrally acting muscle relaxant activity. In addition, the activities of each enantiomer (28-(S) and (R)) were studied along with their acute toxicities. Compound 28-(R) was found to exhibit more potent activity and weaker acute toxicity than 28-(S). Accordingly, compound 28-(R) (NK433) is under development as a novel centrally acting muscle relaxant.
- Shiozawa,Narita,Izumi,Kurashige,Sakitama,Ishikawa
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Read Online
- Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria
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Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.
- Yang, Yiqing,Yu, You,Li, Xiaolu,Li, Jing,Wu, Yue,Yu, Jie,Ge, Jingpeng,Huang, Zhenghui,Jiang, Lubin,Rao, Yu,Yang, Maojun
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supporting information
p. 1994 - 2005
(2017/03/17)
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- COMPOSITIONS CONTAINING, METHODS INVOLVING, AND USES OF NON-NATURAL AMINO ACIDS AND POLYPEPTIDES
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Disclosed herein are non-natural amino acids and polypeptides that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The non-natural amino acids, by themselves or as a part of a polypeptide, can include a wide range of possible functionalities, but typical have at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Also disclosed herein are non-natural amino acid polypeptides that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such polypeptides. Typically, the modified non-natural amino acid polypeptides include at least one oximine, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid polypeptides and modified non-natural amino acid polypeptides, including therapeutic, diagnostic, and other biotechnology uses.
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Paragraph 0525
(2016/07/27)
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- Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
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Background and Purpose: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. Experimental Approach: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3?mg·kg?1) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. Key Results: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. Conclusions and Implications: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood–brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
- Mayer,Wimmer,Dillon-Carter,Partilla,Burchardt,Mihovilovic,Baumann,Sitte
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supporting information
p. 2657 - 2668
(2016/10/19)
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- PHENAZINE AND QUINOXALINE SUBSTITUTED AMINO ACIDS AND POLYPEPTIDES
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Disclosed herein are non-natural amino acids and polypeptides that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The non-natural amino acids, by themselves or as a part of a polypeptide, can include a phenazine or quinoxaline substituent. Also disclosed herein are non-natural amino acid polypeptides that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such polypeptides.
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Page/Page column 170
(2008/12/07)
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- Synthesis, resolution and absolute configuration of a tolperisone metabolite
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1-(4′-Hydroxymethyl-phenyl)-2-methyl-3-(piperidine-1-yl)-propane-1-one M2, a metabolite of tolperisone, was synthesised in a solvent-free Mannich reaction. The optical resolution was carried out by diastereoisomeric salt formation and separation, for which three resolving agents ((2R,3R)-O,O′-dibenzoyl tartaric acid, (2R,3R)-O,O′-di-p-toluoyl tartaric acid and (R)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinane-2- oxide (anicyphos)) were found. The absolute configuration of M2 was determined by the single-crystal X-ray diffraction method.
- Balint, Jozsef,Markovits, Imre,Egri, Gabriella,Tuza, Zsuzsanna,Parkanyi, Laszlo,Fogassy, Elemer
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p. 719 - 724
(2007/10/03)
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