- Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
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A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.
- Yuan, Yunyun,Zaidi, Saheem A.,Stevens, David L.,Scoggins, Krista L.,Mosier, Philip D.,Kellogg, Glen E.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
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supporting information
p. 1701 - 1715
(2015/03/30)
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- CHEMICAL COMPOUNDS
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A compound which is a pyridine or isoquinoline derivative of formula (I), or a pharmaceutically acceptable salt thereof, which is useful in the inhibition of γ- butyrobetaine hydroxylase (BBOX). The compounds are particularly useful in treatment of cardio
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Page/Page column 45
(2015/07/07)
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- Structure activity relationship studies of 17-cyclopropylmethyl-3,14β- dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido) morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
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17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α- (isoquinoline-3′-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1′- or 4′-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQ analogues retained low efficacy at the MOR compared to NAQ in the 35S- GTP[γS] binding assays while electron-withdrawing groups at 1′-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1′- or 4′-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation.
- Yuan, Yunyun,Elbegdorj, Orgil,Beletskaya, Irina O.,Selley, Dana E.,Zhang, Yan
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supporting information
p. 5045 - 5048
(2013/09/12)
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- Assay platform for clinically relevant metallo-β-lactamases
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Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (Sa?o Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors.
- Van Berkel, Sander S.,Brem, Jürgen,Rydzik, Anna M.,Salimraj, Ramya,Cain, Ricky,Verma, Anil,Owens, Raymond J.,Fishwick, Colin W.G.,Spencer, James,Schofield, Christopher J.
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supporting information
p. 6945 - 6953
(2013/10/01)
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- Using NMR solvent water relaxation to investigate metalloenzyme - Ligand binding interactions
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This report demonstrates that solvent water relaxation measurements can be used for quantitative screening of ligand binding and for mechanistic investigations of enzymes containing paramagnetic metal centers by using conventional NMR instrumentation at high field. The method was exemplified using prolyl hydroxylase domain containing enzyme 2 (PHD2), a human enzyme involved in hypoxic sensing, with Mn(II) substituting for Fe(II) at the active site. KD values were determined for inhibitors that hinder access of water to the paramagnetic center. This technique is also useful for investigating the mechanism of suitable metalloenzymes, including order of ligand binding and modes of inhibition. 2009 American Chemical Society.
- Leung, Ivanhoe K. H.,Flashman, Emily,Yeoh, Kar Kheng,Schofield, Christopher J.,Claridge, Timothy D. W.
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supporting information; experimental part
p. 867 - 875
(2010/07/05)
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- Application of a proteolysis/mass spectrometry method for investigating the effects of inhibitors on hydroxylase structure
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Limited proteolysis coupled to matrix-assisted laser desorption/ionization (MALDI) mass spectrometric analyses can be used to screen for compounds that alter protein structure by monitoring stabilizing/destabilizing effects with respect to the rate and na
- Stubbs, Christopher J.,Loenarz, Christoph,Mecinovi?, Jasmin,Kar, Kheng Yeoh,Hindley, Nicola,Liénard, Beno?t M.,Sobott, Frank,Schofield, Christopher J.,Flashman, Emily
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supporting information; experimental part
p. 2799 - 2805
(2010/03/03)
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- Novel nitrogen-containing heteroaryl compounds and methods of use thereof
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The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.
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- Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals
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Novel isoquinoline-3-carboxamides of the formula I: in which R1 is hydrogen or chlorine, R2 is hydrogen, alkyl, alkoxy, chlorine, trifluoromethyl, hydroxyl, or benzyloxy which is optionally substituted, or fluoroalkoxy of the formula O-[CH2]x-CfH(2f+1-g)Fg, where x=0 or 1, f=1-5, and g=1 to (2f+1), R3 is hydrogen, alkyl, alkoxy, fluorine, chlorine, cyano, trifluoromethyl, hydroxyl, or benzyloxy which is optionally substituted, or fluoroalkoxy of the above formula, R4 and R5 are hydrogen, alkyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, alkoxy, or fluoroalkoxy of the above formula, including the physiologically active salts, are strong prolyl-4-hydroxylase inhibitors which do not cause steatosis.
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