title: Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates.
abstract: Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/nucleotides are associated with new directions for therapeutics. The X-ray structures of the A2AAR complexes with agonists and antagonists are examined in relationship to the G-protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies now are explainable from the A2AAR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g., molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for central nervous system and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e., P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, USA. kajacobs@helix.nih.gov
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D055808:Drug Discovery; D005456:Fluorescent Dyes; D057166:High-Throughput Screening Assays; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D058726:Nanoconjugates; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D058470:Receptors, Purinergic P2Y / Q000187:drug effects*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D008024:Ligands; D058726:Nanoconjugates; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled; D018047:Receptors, Purinergic P1; D058470:Receptors, Purinergic P2Y; D054852:Small Molecule Libraries