المؤلفون: López Ó; Department of Organic Chemistry, University of Seville, Profesor García González 1, 41012 Seville, Spain., Qing FL, Pedersen CM, Bols M

المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2013 Aug 15; Vol. 21 (16), pp. 4755-61. Date of Electronic Publication: 2013 Mar 15.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE

مواضيع طبية MeSH: Enzyme Inhibitors/*metabolism , Glycoside Hydrolases/*metabolism , Imino Sugars/*metabolism, Aza Compounds/chemistry ; Catalytic Domain ; Enzyme Inhibitors/chemistry ; Glycoside Hydrolases/antagonists & inhibitors ; Hydrogen-Ion Concentration ; Imino Sugars/chemistry ; Kinetics ; Protein Binding ; Protons

مستخلص: Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes with three (EH3I), two (EH2I), one (EHI), or no protons (EI), are possible. In the present work an analysis method is presented that from pH-inhibition data allows one to distinguish between the different complexes and determine which protonation state is preferred. It is also possible to determine the pH-independent binding constants of the inhibitor. Analysis of pH data for imino- and azasugar inhibition of β-glucosidases revealed that basic glycosidase inhibitors bind as the monoprotonated (EHI) complex. Three neutral inhibitors were also studied and two of these were also bound exclusively as the EHI complex while a third bound both as a EHI and a EH2I complex.
(Copyright © 2013 Elsevier Ltd. All rights reserved.)

المؤلفون: Nielsen S; Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark., Pedersen CM, Hansen SG, Petersen MD, Sinning S, Wiborg O, Jensen HH, Bols M

المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 Jul 15; Vol. 17 (14), pp. 4900-9. Date of Electronic Publication: 2009 Jun 10.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE

مواضيع طبية MeSH: Dopamine Plasma Membrane Transport Proteins/*metabolism , Norepinephrine Plasma Membrane Transport Proteins/*metabolism , Serotonin Plasma Membrane Transport Proteins/*metabolism , Tropanes/*chemistry , Tropanes/*pharmacology, Binding, Competitive ; Diamines/chemical synthesis ; Diamines/chemistry ; Diamines/pharmacology ; Dimerization ; Humans ; Molecular Structure ; Protein Binding ; Structure-Activity Relationship ; Tropanes/chemical synthesis

مستخلص: A series of dimeric phenyl tropanes consisting of two molecules of 4-chloro, 4-iodo or 4-(3-thiopheno)-phenyl tropane tethered together at the carboxylic acid moiety by a diamine or diol linker were prepared. The diamines used were a variety of linear, cyclic and aromatic diamines, while the diol tethered compounds were prepared by 'click' chemistry and contained a triazole in the linker. The new compounds were tested for binding to hDAT, hSERT and hNET. Amide linked chlorophenyl tropanes with an aromatic linker was found to be potent and selective DAT inhibitors with the best K(i) value for hDAT being 6nM. The ester linked halophenyl tropanes were more potent but displayed little selectivity in inhibition of monoamine transporter binding. Among the studied compounds an ester linker of 10 atoms between the tropane moieties gave the highest affinity. One monomeric phenyl tropane was made for comparison and was found to be less potent than the dimeric counterparts towards SERT and NET but remain highly active against DAT. Dimeric thiophenophenyl tropanes were in general found to be comparatively poor monoamine transporter binders, but significant gains of affinity of up to 45-fold could be achieved with selected dimeric chlorophenyl tropanes compared to the parent monomer. This observation implies that a secondary binding site that has affinity for phenyl tropanes, most likely the putative S2 site, is located within 13A of the primary central S1 binding site.