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Author (up) Arias, H.R. file  url
openurl 
  Title Positive and negative modulation of nicotinic receptors Type Journal Article
  Year 2010 Publication Advances in Protein Chemistry and Structural Biology Abbreviated Journal Adv Protein Chem Struct Biol  
  Volume 80 Issue Pages 153-203  
  Keywords Acetylcholine/chemistry/physiology; Allosteric Regulation; Allosteric Site/genetics; Animals; Cholinergic Antagonists/*pharmacology/therapeutic use; Crystallography, X-Ray; Humans; Ion Channel Gating/drug effects; Mice; Nicotinic Agonists/*pharmacology/therapeutic use; Protein Structure, Tertiary; Receptors, Nicotinic/*chemistry/*physiology; Structure-Activity Relationship  
  Abstract Nicotinic acetylcholine receptors (AChRs) are one of the best characterized ion channels from the Cys-loop receptor superfamily. The study of acetylcholine binding proteins and prokaryotic ion channels from different species has been paramount for the understanding of the structure-function relationship of the Cys-loop receptor superfamily. AChR function can be modulated by different ligand types. The neurotransmitter ACh and other agonists trigger conformational changes in the receptor, finally opening the intrinsic cation channel. The so-called gating process couples ligand binding, located at the extracellular portion, to the opening of the ion channel, located at the transmembrane region. After agonist activation, in the prolonged presence of agonists, the AChR becomes desensitized. Competitive antagonists overlap the agonist-binding sites inhibiting the pharmacological action of agonists. Positive allosteric modulators (PAMs) do not bind to the orthostetic binding sites but allosterically enhance the activity elicited by agonists by increasing the gating process (type I) and/or by decreasing desensitization (type II). Instead, negative allosteric modulators (NAMs) produce the opposite effects. Interestingly, this negative effect is similar to that found for another class of allosteric drugs, that is, noncompetitive antagonists (NCAs). However, the main difference between both categories of drugs is based on their distinct binding site locations. Although both NAMs and NCAs do not bind to the agonist sites, NACs bind to sites located in the ion channel, whereas NAMs bind to nonluminal sites. However, this classification is less clear for NAMs interacting at the extracellular-transmembrane interface where the ion channel mouth might be involved. Interestingly, PAMs and NAMs might be developed as potential medications for the treatment of several diseases involving AChRs, including dementia-, skin-, and immunological-related diseases, drug addiction, and cancer. More exciting is the potential combination of specific agonists with specific PAMs. However, we are still in the beginning of understanding how these compounds act and how these drugs can be used therapeutically.  
  Call Number Serial 1886  
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Author (up) Cox, D.; Brennan, M.; Moran, N. file  url
openurl 
  Title Integrins as therapeutic targets: lessons and opportunities Type Journal Article
  Year 2010 Publication Nature Reviews. Drug Discovery Abbreviated Journal Nat Rev Drug Discov  
  Volume 9 Issue 10 Pages 804-820  
  Keywords Animals; Drug Delivery Systems/*methods/trends; Humans; Integrins/*antagonists & inhibitors/*chemistry/physiology; Neoplasms/drug therapy/metabolism; Structure-Activity Relationship  
  Abstract The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets.  
  Call Number Serial 1190  
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Author (up) Gao, J.; Kuczera, K.; Tidor, B.; Karplus, M. file  url
openurl 
  Title Hidden thermodynamics of mutant proteins: a molecular dynamics analysis Type Journal Article
  Year 1989 Publication Science (New York, N.Y.) Abbreviated Journal Science  
  Volume 244 Issue 4908 Pages 1069-1072  
  Keywords Alanine; Asparagine; Hemoglobins/*genetics; Hydrogen Bonding; Macromolecular Substances; Molecular Structure; *Mutation; Oxyhemoglobins; Structure-Activity Relationship; Thermodynamics  
  Abstract A molecular dynamics simulation method is used to determine the contributions of individual amino acid residues and solvent molecules to free energy changes in proteins. Its application to the hemoglobin interface mutant Asp G1(99) beta----Ala shows that some of the contributions to the difference in the free energy of cooperativity are as large as 60 kilocalories (kcal) per mole. Since the overall free energy change is only -5.5 kcal/mole (versus the experimental value of -3.4 kcal/mole), essential elements of the thermodynamics are hidden in the measured results. By exposing the individual contributions, the free energy simulation provides new insights into the origin of thermodynamic changes in mutant proteins and demonstrates the role of effects beyond those usually considered in structural analyses.  
  Call Number Serial 1709  
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Author (up) Jiang, J.-K.; Thomas, C.J.; Neumann, S.; Lu, X.; Rice, K.C.; Gershengorn, M.C. file  url
doi  openurl
  Title 1-(Phenyl)isoquinoline carboxamides: a novel class of subtype selective inhibitors of thyrotropin-releasing hormone (TRH) receptors Type Journal Article
  Year 2005 Publication Bioorganic & Medicinal Chemistry Letters Abbreviated Journal Bioorg Med Chem Lett  
  Volume 15 Issue 3 Pages 733-736  
  Keywords Amides/*chemical synthesis/pharmacology; Animals; Binding, Competitive; Isoquinolines/chemical synthesis/*pharmacology; Ligands; Mice; Radioligand Assay; Receptors, Thyrotropin-Releasing Hormone/*antagonists & inhibitors; Structure-Activity Relationship  
  Abstract We report the synthesis of and binding to the two subtypes of mouse thyrotropin-releasing hormone (TRH) receptors, TRH-R1 and TRH-R2, of several 1-(phenyl)isoquinoline carboxamide analogues. These analogues showed a degree of selectivity for binding at TRH-R2. These are the first ligands reported that show selective binding to these receptors.  
  Call Number Serial 246  
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Author (up) Jiang, J.-K.; Thomas, C.J.; Neumann, S.; Lu, X.; Rice, K.C.; Gershengorn, M.C. file  url
doi  openurl
  Title 1-(Phenyl)isoquinoline carboxamides: a novel class of subtype selective inhibitors of thyrotropin-releasing hormone (TRH) receptors Type Journal Article
  Year 2005 Publication Bioorganic & Medicinal Chemistry Letters Abbreviated Journal Bioorg Med Chem Lett  
  Volume 15 Issue 3 Pages 733-736  
  Keywords Amides/*chemical synthesis/pharmacology; Animals; Binding, Competitive; Isoquinolines/chemical synthesis/*pharmacology; Ligands; Mice; Radioligand Assay; Receptors, Thyrotropin-Releasing Hormone/*antagonists & inhibitors; Structure-Activity Relationship  
  Abstract We report the synthesis of and binding to the two subtypes of mouse thyrotropin-releasing hormone (TRH) receptors, TRH-R1 and TRH-R2, of several 1-(phenyl)isoquinoline carboxamide analogues. These analogues showed a degree of selectivity for binding at TRH-R2. These are the first ligands reported that show selective binding to these receptors.  
  Call Number Serial 399  
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Author (up) Lill, A.P.; Rodl, C.B.; Steinhilber, D.; Stark, H.; Hofmann, B. file  url
openurl 
  Title Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy Type Journal Article
  Year 2015 Publication European Journal of Medicinal Chemistry Abbreviated Journal Eur J Med Chem  
  Volume 89 Issue Pages 503-523  
  Keywords Arachidonate 5-Lipoxygenase/*metabolism; Dose-Response Relationship, Drug; Humans; Leukotriene Antagonists/chemical synthesis/chemistry/*pharmacology; Leukotrienes/*metabolism; Lipoxygenase Inhibitors/chemical synthesis/chemistry/*pharmacology; Molecular Structure; Structure-Activity Relationship; Thiazoles/chemical synthesis/chemistry/*pharmacology; 5-Lipoxygenase; Anti-leukotriene therapy; Hydroxythiazoles; Inflammation; Solubility; Structure-activity relationship  
  Abstract Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 muM) and cell-free assays (IC50 values 0.03 muM) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.  
  Call Number Serial 1464  
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Author (up) Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J. file  url
openurl 
  Title Natural and non-natural prenylated chalcones: synthesis, cytotoxicity and anti-oxidative activity Type Journal Article
  Year 2008 Publication Bioorganic & Medicinal Chemistry Abbreviated Journal Bioorg Med Chem  
  Volume 16 Issue 8 Pages 4286-4293  
  Keywords Antioxidants/*chemical synthesis/chemistry/*toxicity; Biological Products/*chemistry/*toxicity; Cell Survival/drug effects; Chalcones/*chemical synthesis/chemistry/*toxicity; HeLa Cells; Humans; Molecular Structure; Prenylation; Structure-Activity Relationship  
  Abstract A general strategy for the synthesis of 3'-prenylated chalcones was established and a series of prenylated hydroxychalcones, including the hop (Humulus lupulus L.) secondary metabolites xanthohumol (1), desmethylxanthohumol (2), xanthogalenol (3), and 4-methylxanthohumol (4) were synthesized. The influence of the A-ring hydroxylation pattern on the cytotoxic activity of the prenylated chalcones was investigated in a HeLa cell line and revealed that non-natural prenylated chalcones, like 2',3,4',5-tetrahydroxy-6'-methoxy-3'-prenylchalcone (9, IC(50) 3.2+/-0.4microM) as well as the phase 1 metabolite of xanthohumol (1), 3-hydroxyxanthohumol (8, IC(50) 2.5+/-0.5microM), were more active in comparison to 1 (IC(50) 9.4+/-1.4microM). A comparison of the cytotoxic activity of xanthohumol (1) and 3-hydroxyxanthohumol (8) with the non-prenylated analogs helichrysetin (12, IC(50) 5.2+/-0.8) and 3-hydroxyhelichrysetin (13, IC(50) 14.8+/-2.1) showed that the prenyl side chain at C-3' has an influence on the cytotoxicity against HeLa cells only for the dihydroxylated derivative. This offers interesting synthetic possibilities for the development of more potent compounds. The ORAC activity of the synthesized compounds was also investigated and revealed the highest activity for compounds 12, 4'-methylxanthohumol (4), and desmethylxanthohumol (2), with 4.4+/-0.6, 3.8+/-0.4, and 3.8+/-0.5 Trolox equivalents, respectively.  
  Call Number USED BY MULTIPLE STUDENTS Serial 1056  
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