Kenneth A Jacobson

Summary

Affiliation: National Institutes of Health
Country: USA

Publications

  1. ncbi request reprint Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M(3) muscarinic acetylcholine receptor
    Sung Jun Han
    Molecular Signaling and Molecular Recognition Sections, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Biol Chem 280:34849-58. 2005
  2. pmc Probing the binding site of the A1 adenosine receptor reengineered for orthogonal recognition by tailored nucleosides
    Krishnan K Palaniappan
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    Biochemistry 46:7437-48. 2007
  3. ncbi request reprint Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A(1) and A(3) adenosine receptors
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD 20892 0810, USA
    Biochem Pharmacol 65:525-34. 2003
  4. doi request reprint Ligand-specific changes in M3 muscarinic acetylcholine receptor structure detected by a disulfide scanning strategy
    Jian Hua Li
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, 8 Center Drive, Bethesda, Maryland 20892 0810, USA
    Biochemistry 47:2776-88. 2008
  5. ncbi request reprint Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    Nucleosides Nucleotides Nucleic Acids 25:1425-36. 2006
  6. ncbi request reprint Pronounced conformational changes following agonist activation of the M(3) muscarinic acetylcholine receptor
    Sung Jun Han
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 280:24870-9. 2005
  7. pmc Selective A(3) adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system
    Artem Melman
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A 19, Bethesda, MD 20892, USA
    Bioorg Med Chem 16:8546-56. 2008
  8. ncbi request reprint Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands
    Jian Hua Li
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Biol Chem 282:26284-93. 2007
  9. pmc Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 50:1166-76. 2007
  10. ncbi request reprint Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892 0810, USA
    Mol Pharmacol 63:1021-31. 2003

Detail Information

Publications77

  1. ncbi request reprint Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M(3) muscarinic acetylcholine receptor
    Sung Jun Han
    Molecular Signaling and Molecular Recognition Sections, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Biol Chem 280:34849-58. 2005
    ..To the best of our knowledge, this is the first direct demonstration of a conformational change occurring in the immediate vicinity of the binding site of a GPCR activated by a diffusible ligand...
  2. pmc Probing the binding site of the A1 adenosine receptor reengineered for orthogonal recognition by tailored nucleosides
    Krishnan K Palaniappan
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    Biochemistry 46:7437-48. 2007
    ..This neoceptor approach should be useful for the validation of molecular modeling and the dissection of promiscuous GPCR signaling...
  3. ncbi request reprint Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A(1) and A(3) adenosine receptors
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD 20892 0810, USA
    Biochem Pharmacol 65:525-34. 2003
    ..Both binding and functional assays support the allosteric interactions of amiloride analogues with A(3) receptors...
  4. doi request reprint Ligand-specific changes in M3 muscarinic acetylcholine receptor structure detected by a disulfide scanning strategy
    Jian Hua Li
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, 8 Center Drive, Bethesda, Maryland 20892 0810, USA
    Biochemistry 47:2776-88. 2008
    ..Because all class I GPCRs are predicted to share a similar transmembrane topology, the conclusions drawn from the present study should be of broad general relevance...
  5. ncbi request reprint Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    Nucleosides Nucleotides Nucleic Acids 25:1425-36. 2006
    ..Using a rational design process we have identified neoceptor-neoligand pairs which are pharmacologically orthogonal with respect to the native species...
  6. ncbi request reprint Pronounced conformational changes following agonist activation of the M(3) muscarinic acetylcholine receptor
    Sung Jun Han
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 280:24870-9. 2005
    ..These findings should be of relevance for other family A GPCRs...
  7. pmc Selective A(3) adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system
    Artem Melman
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A 19, Bethesda, MD 20892, USA
    Bioorg Med Chem 16:8546-56. 2008
    ..7-1.4 nM. In a functional assay of [35S]GTPcS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a KB of 8.9 nM. Thus, a highly potent and selective series of A3AR antagonists has been described...
  8. ncbi request reprint Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands
    Jian Hua Li
    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Biol Chem 282:26284-93. 2007
    ..Given the high degree of structural homology found among most G protein-coupled receptors, our findings should be of broad general relevance...
  9. pmc Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 50:1166-76. 2007
    ..This detailed view of P2Y2 receptor recognition suggests mutations for model validation...
  10. ncbi request reprint Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892 0810, USA
    Mol Pharmacol 63:1021-31. 2003
    ..1-i]purin-5-one (PSB-11) at the WT A(3)ARs, but not the D58N(2.50) mutant receptor. The results were interpreted using a rhodopsin-based molecular model of the A(3)AR to suggest multiple binding modes of the allosteric modulators...
  11. ncbi request reprint 2,2'-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 0810, USA
    Biochem Pharmacol 68:231-7. 2004
    ..Thus, PIT selectively and non-competitively blocked P2Y(1) receptor signaling without affecting nucleotide binding...
  12. pmc Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system
    Dilip K Tosh
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 52:7580-92. 2009
    ..SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K(i) = 2.1 nM) and truncated partial agonist 22 (K(i) = 4.9 nM)...
  13. pmc A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    Chem Biol 12:237-47. 2005
    ..Thus, we identified and modeled pairs of A(2A)AR-derived neoceptor-neoligand, which are pharmacologically orthogonal with respect to the native species...
  14. ncbi request reprint Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor
    Soo Kyung Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, National Institutes of Health NIH, Bethesda, MD 20892, USA
    J Mol Graph Model 25:562-77. 2006
    ..Thus, the putative conformational changes associated with A(3)AR activation indicate a shared mechanism of GPCR activation similar to rhodopsin...
  15. pmc Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 49:2689-702. 2006
    ..The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene...
  16. pmc (N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists
    Susanna Tchilibon
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 48:1745-58. 2005
    ..Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists...
  17. ncbi request reprint Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptors
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Biochem Pharmacol 71:540-9. 2006
    ....
  18. doi request reprint Probing distal regions of the A2B adenosine receptor by quantitative structure-activity relationship modeling of known and novel agonists
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    J Med Chem 51:2088-99. 2008
    ..Thus, in support of the modeling, bulky substitutions at both positions did not prevent A 2B AR activation, which predicts separate regions for docking of these moieties...
  19. pmc Molecular recognition in the P2Y(14) receptor: Probing the structurally permissive terminal sugar moiety of uridine-5'-diphosphoglucose
    Hyojin Ko
    Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD 20892, USA
    Bioorg Med Chem 17:5298-311. 2009
    ..1.0]hexane groups abolished activity. Uridine-5'-diphosphoglucose also activates the P2Y(2) receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y(14)-selective...
  20. ncbi request reprint Structural determinants of A(3) adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 45:4471-84. 2002
    ..Thus, A(3)AR activation appeared to require flexibility at the 5'- and 3'-positions, which was diminished in (N)-methanocarba, spiro, and epoxide analogues, and was characteristic of ribose interactions at TM6 and TM7...
  21. pmc Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety
    Zhan Guo Gao
    Laboratory of Bioorganic Chemistry, Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Biochem Pharmacol 67:893-901. 2004
    ....
  22. pmc 2-Dialkynyl derivatives of (N)-methanocarba nucleosides: 'Clickable' A(3) adenosine receptor-selective agonists
    Dilip K Tosh
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8A, Rm B1A 19, NIH, NIDDK, LBC, Bethesda, MD 20892, United States
    Bioorg Med Chem 18:508-17. 2010
    ..Thus, this strategy provides a general chemical approach to linking potent and selective A(3)AR agonists to reporter groups of diverse structure and to carrier moieties...
  23. ncbi request reprint Molecular recognition at adenine nucleotide (P2) receptors in platelets
    Kenneth A Jacobson
    Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 0810, USA
    Semin Thromb Hemost 31:205-16. 2005
    ..The P2Y (1) receptor model, especially, has been exploited in the design and optimization of antagonists targeted to interact selectively with that subtype...
  24. pmc 2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists
    Hak Sung Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892 0810, USA
    J Med Chem 46:4974-87. 2003
    ..An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored...
  25. pmc Polyamidoamine (PAMAM) dendrimer conjugates of "clickable" agonists of the A3 adenosine receptor and coactivation of the P2Y14 receptor by a tethered nucleotide
    Dilip K Tosh
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    Bioconjug Chem 21:372-84. 2010
    ..Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment...
  26. pmc Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Bioorg Med Chem Lett 16:596-601. 2006
    ..Competitive antagonism was demonstrated by Schild analysis. The 2-(dimethylamino)-5'-(N,N-dimethyl)uronamido substitution also retained A(3)AR selectivity but lowered affinity...
  27. pmc Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptor
    Hyojin Ko
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 50:2030-9. 2007
    ..The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification...
  28. pmc Structure-activity relationships of 2,N(6),5'-substituted adenosine derivatives with potent activity at the A2B adenosine receptor
    Hayamitsu Adachi
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Med Chem 50:1810-27. 2007
    ..Compound 28 was a full agonist at A2B and A2AARs and a low efficacy partial agonist at A1 and A3ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A2BAR potency and selectivity...
  29. pmc Evaluation of homology modeling of G-protein-coupled receptors in light of the A(2A) adenosine receptor crystallographic structure
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 52:3284-92. 2009
    ..Thus, homology modeling of GPCRs remains a useful technique in probing the structure of the protein and predicting modes of ligand docking...
  30. ncbi request reprint Selective allosteric enhancement of agonist binding and function at human A3 adenosine receptors by a series of imidazoquinoline derivatives
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    Mol Pharmacol 62:81-9. 2002
    ..Thus, we have identified a novel structural lead for developing allosteric enhancers of A3 adenosine receptors; such enhancers may be useful for treating brain ischemia and other hypoxic conditions...
  31. pmc Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor
    Yoonkyung Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 52:2098-108. 2009
    ....
  32. pmc Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups
    Arijit Das
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 53:471-80. 2010
    ..92 nM) was 2160-fold selective versus P2Y(6). Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor...
  33. pmc Design of (N)-methanocarba adenosine 5'-uronamides as species-independent A3 receptor-selective agonists
    Artem Melman
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A 19, Bethesda, MD 20892 0810, USA
    Bioorg Med Chem Lett 18:2813-9. 2008
    ..Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A(3)AR selectivity more effectively than similar chains attached at the 3-position of the N(6)-benzyl group...
  34. ncbi request reprint Modeling the adenosine receptors: comparison of the binding domains of A2A agonists and antagonists
    Soo Kyung Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, National Institutes of Health NIH, Bethesda, Maryland 20892, USA
    J Med Chem 46:4847-59. 2003
    ..We identified new neoceptor (T88D)-neoligand pairs that were consistent with the model...
  35. ncbi request reprint Effects of the allosteric modulator SCH-202676 on adenosine and P2Y receptors
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD 20892 0810, USA
    Life Sci 74:3173-80. 2004
    ..Thus, SCH-202676 differentially modulated A(1), A(2A), and A(3) receptors as well as agonist- and antagonist-occupied receptors...
  36. pmc N6-Substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Room B1A 19, Building 8A, Bethesda, MD 20892, USA
    Biochem Pharmacol 65:1675-84. 2003
    ..63nM) than rat A(3)ARs. Dual acting A(1)/A(3) agonists (N(6)-3-chlorobenzyl- 29, N(6)-(S-1-phenylethyl)- 39, and 2-chloro-N(6)-(R-phenylisopropyl)adenosine 53) might be useful for cardioprotection...
  37. pmc "Reversine" and its 2-substituted adenine derivatives as potent and selective A3 adenosine receptor antagonists
    Melissa Perreira
    Chemical Biology Core Facility, and Molecular Recognition Section, Laboratory of Biological Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 48:4910-8. 2005
    ..We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation...
  38. pmc Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection
    Kenneth A Jacobson
    National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 48:8103-7. 2005
    ..Consequently, 2 was balanced in affinity and potency at A(1)/A(3)ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion...
  39. pmc Neoceptors: reengineering GPCRs to recognize tailored ligands
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases NIDDK, National Institutes of Health NIH, Bethesda, MD 20892, USA
    Trends Pharmacol Sci 28:111-6. 2007
    ..The neoceptor-neoligand pairing could offer spatial specificity by delivering the neoceptor to a target site, and temporal specificity by administering neoligand when needed...
  40. pmc Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    BMC Pharmacol 8:20. 2008
    ..Here we studied the modulation by LUF6000 of the maximum effect (Emax) of structurally diverse agonists at the A3 AR stably expressed in CHO cells...
  41. pmc 2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Biochem Pharmacol 68:1985-93. 2004
    ..4 microM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC(50) = 1.8 microM) were found to be relatively potent A(2B) agonists, although less potent than NECA (EC(50) = 140 nM)...
  42. ncbi request reprint Random mutagenesis of the M3 muscarinic acetylcholine receptor expressed in yeast: identification of second-site mutations that restore function to a coupling-deficient mutant M3 receptor
    Bo Li
    Department of Molecular Signaling, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, 8 Center Dr, Bethesda, MD 20892, USA
    J Biol Chem 280:5664-75. 2005
    ..Our data suggest a conformational link between the highly conserved Asp-113, Arg-165, and Tyr-250 residues which is critical for receptor activation...
  43. ncbi request reprint Adenine nucleotide analogues locked in a Northern methanocarba conformation: enhanced stability and potency as P2Y(1) receptor agonists
    R Gnana Ravi
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases NIH, Building 8A, Room B1A 17, Bethesda, MD 20892 0810, USA
    J Med Chem 45:2090-100. 2002
    ..This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y(1) receptors...
  44. pmc Architecture of P2Y nucleotide receptors: structural comparison based on sequence analysis, mutagenesis, and homology modeling
    Stefano Costanzi
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Med Chem 47:5393-404. 2004
    ..35. Thus, we have identified common and distinguishing features of P2Y receptor structure and have proposed modes of ligand binding for the two representative subtypes that already have well-developed ligands...
  45. doi request reprint Synthesis of ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxy-bicyclo[3.1.0]hexane-carboxylate from L-ribose: a versatile chiral synthon for preparation of adenosine and P2 receptor ligands
    Bhalchandra V Joshi
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892 0810, USA
    Nucleosides Nucleotides Nucleic Acids 27:279-91. 2008
    ..Improvements were made in subsequent steps corresponding to a published route to biologically important (N)-methanocarba 5'-uronamido nucleosides, and new steps were added to prepare related 5'-nucleotides...
  46. pmc Multivalent dendrimeric and monomeric adenosine agonists attenuate cell death in HL-1 mouse cardiomyocytes expressing the A(3) receptor
    Athena M Keene
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 0810, USA
    Biochem Pharmacol 80:188-96. 2010
    ..Thus, a PAMAM conjugate retained AR binding affinity and displayed greatly enhanced cardioprotective potency...
  47. pmc Molecular dynamics simulation of the P2Y14 receptor. Ligand docking and identification of a putative binding site of the distal hexose moiety
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Bioorg Med Chem Lett 17:761-6. 2007
    ..55) and Lys277 (7.35) of the P2Y14 receptor together with two anionic residues (Glu166 and Glu174, located in EL2), are likely involved in interactions with the distal hexose moiety...
  48. ncbi request reprint Three-dimensional quantitative structure-activity relationship of nucleosides acting at the A3 adenosine receptor: analysis of binding and relative efficacy
    Soo Kyung Kimand
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, National Institutes of Health NIH, Bethesda, Maryland 20892, USA
    J Chem Inf Model 47:1225-33. 2007
    ....
  49. ncbi request reprint Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions
    Soon Ai Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Med Chem 45:2131-8. 2002
    ..In conclusion, new leads for the design of xanthines substituted in the 1-, 3-, 7-, and 8-positions as A2B receptor-selective antagonists have been identified...
  50. ncbi request reprint Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors
    Hak Sung Kim
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Med Chem 45:208-18. 2002
    ..Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y1, P2Y2, P2Y4, and P2Y11 receptors...
  51. pmc Structure-activity relationship of (N)-Methanocarba phosphonate analogues of 5'-AMP as cardioprotective agents acting through a cardiac P2X receptor
    T Santhosh Kumar
    Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 0810, USA
    J Med Chem 53:2562-76. 2010
    ..Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure...
  52. pmc Activation of distinct P2Y receptor subtypes stimulates insulin secretion in MIN6 mouse pancreatic beta cells
    Ramachandran Balasubramanian
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD, USA
    Biochem Pharmacol 79:1317-26. 2010
    ....
  53. ncbi request reprint Acyclic analogues of adenosine bisphosphates as P2Y receptor antagonists: phosphate substitution leads to multiple pathways of inhibition of platelet aggregation
    Bin Xu
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0810, USA
    J Med Chem 45:5694-709. 2002
    ..Thus, different substitution of the same nucleoside scaffold can target either of two P2Y receptors in platelets...
  54. pmc Molecular modeling of a PAMAM-CGS21680 dendrimer bound to an A2A adenosine receptor homodimer
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Bioorg Med Chem Lett 18:4312-5. 2008
    ..The binding mode of CGS21680 moieties linked to the PAMAM dendrimer and docked to the A(2A) receptor was found to be similar to the binding mode of a monomeric CGS21680 ligand...
  55. ncbi request reprint Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling
    Andrei A Ivanov
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    J Comput Aided Mol Des 20:417-26. 2006
    ..In general, these findings are in agreement with the proposed binding site of small molecules to other class A GPCRs...
  56. pmc Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways
    Zhan Guo Gao
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A 19, Bethesda, MD, USA
    Pharmacol Res 57:303-11. 2008
    ..Thus, lead candidates for biased agonists at the A(3)AR have been identified with this arrestin-translocation assay, which promises to be an effective tool for ligand screening...
  57. ncbi request reprint Emerging adenosine receptor agonists
    Zhan Guo Gao
    NIDDK, National Institutes of Health, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, Bldg 8A, Room B1A 23, 9000 Rockville Pike, Bethesda, Maryland 20892 0810, USA
    Expert Opin Emerg Drugs 12:479-92. 2007
    ..The present review will mainly cover the agonists that are presently in clinical trials for various conditions and only a brief introduction will be given to major chemical classes of AR agonists presently under investigation...
  58. ncbi request reprint Nucleoside modification and concerted mutagenesis of the human A3 adenosine receptor to probe interactions between the 2-position of adenosine analogs and Gln167 in the second extracellular loop
    Heng T Duong
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 0810, USA
    Nucleosides Nucleotides Nucleic Acids 24:1507-17. 2005
    ..The data suggests that a direct contact is made between the C2 substituent of some charged ligands and the mutant receptor bearing the opposite charge at position 167...
  59. ncbi request reprint Molecular recognition at purine and pyrimidine nucleotide (P2) receptors
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Biorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD 20892 0810, USA E mail
    Curr Top Med Chem 4:805-19. 2004
    ..The binding of the negatively-charged phosphate moiety is dependent on positively charged lysine and arginine residues near the exofacial side of TMs 3 and 7...
  60. pmc Development of selective agonists and antagonists of P2Y receptors
    Kenneth A Jacobson
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8A, Rm B1A 19, Bethesda, MD, USA
    Purinergic Signal 5:75-89. 2009
    ..The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets...
  61. pmc Enhanced A3 adenosine receptor selectivity of multivalent nucleoside-dendrimer conjugates
    Athena M Klutz
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
    J Nanobiotechnology 6:12. 2008
    ..abstract:..
  62. ncbi request reprint Purine derivatives as ligands for A3 adenosine receptors
    Bhalchandra V Joshi
    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    Curr Top Med Chem 5:1275-95. 2005
    ..3 nm...
  63. ncbi request reprint Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands
    Liesbet Cosyn
    Laboratory for Medicinal Chemistry FFW, UGent, Belgium
    Bioorg Med Chem 14:1403-12. 2006
    ..For both the 3'-azides and the 3'-amines, the 5'-methylcarbamoyl modification improved the overall affinity. Introduction of a 2-phenylethynyl substituent provided high affinity for the A(3)AR...
  64. ncbi request reprint Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor
    Lak Shin Jeong
    Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120 750, Republic of Korea
    Bioorg Med Chem 14:4718-30. 2006
    ..N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM...
  65. ncbi request reprint Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists
    Christa E Muller
    Pharmaceutical Institute Poppelsdorf, University of Bonn, Bonn, Germany
    J Med Chem 45:3440-50. 2002
    ..The most potent A(3) antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a K(i) value of 2.3 nM and high selectivity for A(3) receptors vs all other AR subtypes...
  66. ncbi request reprint Synthesis of 3'-ureidoadenosine analogues and their binding affinity to the A3 adenosine receptor
    Moon Woo Chun
    Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
    Nucleosides Nucleotides Nucleic Acids 24:1119-21. 2005
    ..However, all synthesized 3'-ureidoadenosine analogues have lost their binding affinities to the all subtypes of adenosine receptors, indicating that bulky 3'-urea moiety led to conformational distortion...
  67. ncbi request reprint Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor
    Lak Shin Jeong
    Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120 750, Korea
    J Med Chem 49:273-81. 2006
    ..In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR...
  68. ncbi request reprint 2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors
    Vita Ozola
    University of Bonn, Pharmaceutical Institute Poppelsdorf, Kreuzbergweg 26, D 53115 Bonn, Germany
    Bioorg Med Chem 11:347-56. 2003
    ..Due to their high A(3) affinity, selectivity, and relatively high water-solubility, 2-phenyl-imidazo[2,1-i]purin-5-ones may become useful research tools...
  69. ncbi request reprint N6-substituted D-4'-thioadenosine-5'-methyluronamides: potent and selective agonists at the human A3 adenosine receptor
    Lak Shin Jeong
    Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120 750, Korea
    J Med Chem 46:3775-7. 2003
    ..28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively...
  70. ncbi request reprint D-4'-thioadenosine derivatives as highly potent and selective agonists at the human A3 adenosine receptor
    Hyouk Woo Lee
    College of Pharmacy, Seoul National University, Seoul corrected Korea
    Nucleosides Nucleotides Nucleic Acids 24:607-9. 2005
    ..28 +/- 0.09 nM) at the human A3 adenosine receptor...
  71. ncbi request reprint Design, synthesis and binding affinity of 3'-fluoro analogues of Cl-IB-MECA as adenosine A3 receptor ligands
    Moo Hong Lim
    College of Pharmacy, Seoul National University, Seoul 151 742, South Korea
    Bioorg Med Chem Lett 13:817-20. 2003
    ....
  72. ncbi request reprint Design and synthesis of 3'-ureidoadenosine-5'-uronamides: effects of the 3'-ureido group on binding to the A3 adenosine receptor
    Lak Shin Jeong
    Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120 750, South Korea
    Bioorg Med Chem Lett 14:4851-4. 2004
    ....
  73. ncbi request reprint New 8-substituted xanthiene derivatives as potent bronchodilators
    Barkin Berk
    Yeditepe University, Faculty of Pharmacy, 26 Agustos Yerlesimi, 34755, Kayisdagi, Istanbul, Turkey
    Farmaco 60:974-80. 2005
    ..Our results showed that these compounds are acting as selective adenosine antagonists, especially for adenosine A2B receptors, and are promising as potent anti-inflammatory agents rather than bronchodilator for the treatment of asthma...
  74. pmc Involvement of uracil nucleotides in protection of cardiomyocytes from hypoxic stress
    Smadar Yitzhaki
    Faculty of Life Sciences, Bar Ilan University, Ramat Gan 52900, Israel
    Biochem Pharmacol 69:1215-23. 2005
    ....
  75. pmc Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety
    Philippe Van Rompaey
    Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences FFW, Ghent University, Harelbekestraat 72, B 9000 Gent, Belgium
    Bioorg Med Chem 13:973-83. 2005
    ..Interesting was the ability to tune the intrinsic activity depending on the substituent introduced at the 3'-position...
  76. ncbi request reprint Progress in the pursuit of therapeutic adenosine receptor antagonists
    Stefano Moro
    Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Universita di Padova, Via Marzolo 5, I 35131 Padova, Italy
    Med Res Rev 26:131-59. 2006
    ..In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists...
  77. pmc Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog
    Mariya Chhatriwala
    University of North Carolina, School of Medicine, Department of Pharmacology, CB 7365, Chapel Hill, NC 27599 7365, USA
    J Pharmacol Exp Ther 311:1038-43. 2004
    ....