Purines in Cellular Signaling: Targets for New Drugs

Research on purine derivatives as potent and selective modulators of physiologic functions has moved to center stage. This volume covers the biology and chemistry of purines and of their receptors broadly under these section headings: - Adenosine Receptors and Effector Systems - Adenine Nucleotide Receptors and Effector Systems - Phosphodiesterase Enzymes and Inhibitors The presentations focus on the potential development of clinically useful drugs and powerful agents that activate or block purinergic receptors or that inhibit phosphodiesterases. Xanthines (caffeine and theophylline) represent one class of such agents. This volume is for pharmacologists, biochemists, and medical chemists in research labs of universities, gov- ernment, and the pharmaceutical industry.

Table of Contents:
Section 1: Adenosine Receptors and Effector Systems.- 1 Adenosine Agonists and Antagonists.- 2 Intracellular and Extracellular Metabolism of Adenosine and Adenine Nucleotides.- 3 Adenosine Deaminase and Adenosine Transport Systems in the CNS.- 4 Transport Systems for Adenosine in Mammalian Cell Membranes.- 5 Formation of Adenosine in the Heart from Extracellular Adenine Nucleotides.- 6 Central Nervous System Effects of Adenosine.- 7 Adenosine Receptor Sub-types in Isolated Tissues: Antagonist Studies.- 8 Molecular Probes for Adenosine Receptors.- 9 Purification of A1 Adenosine Receptor of Rat Brain Membranes by Affinity Chromatography.- 10 Characteristics of A1 Adenosine Receptors and Guanine Nucleotide Binding Proteins Co-Purified from Bovine Brain.- 11 Antagonist Radioligand Binding to Solubilized Porcine Atrial A1 Adenosine Receptors.- 12 Isolation of an Adenosine Binding Protein Which Has Properties Expected of the A1 Adenosine Receptor.- 13 Identification of the A2 Adenosine Receptor Binding Subunit by Photoaffinity Crosslinking.- 14 Human Placental Adenosine A2-Like Binding Sites Properties and Homology with Mammalian and Avian Stress Proteins.- 15 Cardiac Interstitial Fluid Adenosine in Normoxia and Hypoxia.- 16 Rationale for the Use of Adenosine in the Diagnosis and Treatment of Cardiac Arrhythmias.- 17 The Central Adenosine System as a Therapeutic Target in Stroke.- 18 Adenosine-Mediated Vasoconstriction in the Skin Microcirculation.- 19 Adenosine is an Antiinflammatory Autocoid: Adenosine Receptor Occupancy Promotes Neutrophil Chemotaxis and Inhibits Superoxide Anion Generation.- 20 Beta Adrenergic Receptor Mediated Stimulation of Adenine Nucleotide Catabolism and Purine Release in Human Adipocytes.- 21 Structure Activity Relationships for Adenosine Antagonists.- 22 Structure Activity Relationships for Adenosine Agonists.- 23 The Design of a Series of Highly A2 Selective Adenosine Agonists.- 24 Adenosine Agonists. Characterization of the N6-Subregion of the Adenosine A2 Receptor via Molecular Modeling Techniques.- 25 Physiological and Biochemical Aspects of “P”-Site-Mediated Inhibition of Adenylyl Cyclase.- 26 Adenosine Receptors Mediating Inhibition of Peripheral and Central Neurons.- 27 Adenosine Receptors as Drug Targets: Fulfilling the Promise?.- 28 Mechanisms of Adenosine Action.- 29 Functional Roles of A1 and A2 Receptors in Rat Hippocampus and Striatum.- 30 Subclassification of Neuronal Adenosine Receptors.- 31 Effects of Adenosine on Mast Cells.- 32 The Role of Adenosine on the Gastric Acid Secretory Response.- 33 Adenosine Receptors and Signaling in the Kidney.- 34 Inhibition of the Function of Guanine Nucleotide Binding Proteins by the New Positive Inotropes.- 35 Blockade of Antigen Activated Signals by Xanthine Analogs in RBL-2H3 Cells:Evidence for a Novel Adenosine Receptor.- Section 2: Adenine Nucleotide Receptors and Effector Systems.- 36 Classification and Characterization of Purinoceptors.- 37 Structure Activity Relationships for Adenine Nucleotide Receptors on Mast Cells, Human Platelets, and Smooth Muscle.- 38 Modulation of Norepinephrine Release by ATP and Adenosine.- 39 The Phospholipase C Linked P2y-Purinergic Receptor.- 40 Roles of an ADP Receptor on the Platelet Surface in Mediating Aggregation and Fibrinogen Binding.- Section 3: Phosphodiesterase Enzymes and Inhibitors.- 41 Structural and Functional Characterization of Cyclic GMP-Stimulated Phosphodiesterases and Their Role in Intracellular Signal Transduction.- 42 Phosphodiesterase Genes from Flies to Mammals.- 43 Structure and Function of theHigh Affinity, Rolipram and RO 2-1724 Sensitive, cAMP Phosphodiesterases.- 44 Correlation of 3H-Rolipram Binding to a Cerebral cAMP Phosphodiesterase with Antidepressant Activity.- 45 Mechanism for Dual Regulation of the Particulate cGMP-Inhibited cAMP Phosphodiesterase in Rat Adipocytes by Isoproterenol and Insulin.- 46 Expression of Calmodulin-Dependent Cyclic Nucleotide Phosphodiesterase in Developing and Adult Rat Brain.- 47 Regulation of cAMP Metabolism in PC12 Cells by Type II (cGMP-Activatable) Cyclic Nucleotide Phosphodiesterase.- 48 cGMP-Binding Phosphodiesterase: Novel Effects of cGMP Binding on the Interaction Between Functional Domains in the Enzyme.- 49 Clinical Investigations with Phosphodiesterase Inhibitors.- 50 Chemical Probes of Type IV Phosphodiesterase: Design, Synthesis, and Characterization of (3H)-2Y186126 as a Radioligand for Sites Within Cardiac Membranes.- 51 Purification of a cGMP-inhibited cAMP Phosphodiesterase from Vascular Smooth Muscle.- 52 Low KmcAMP Phosphodiesterase Isozymes and Modulation of Tone in Vascular, Airway and Gastrointestinal Smooth Muscle.- 53 Structure Activity Relationships of Xanthines as Inhibitors of Cyclic Nucleotide Phosphodiesterases and as Antagonists of Adenosine Receptors.- 54 Mechanisms of Xanthine Actions in Models of Asthma.- Section 4: Abstracts.- A Intracellular and Extracellular Metabolism of Adenosine and Adenine Nucleotides.- B Molecular Probes for Purinoceptors.- C Phosphodiesterases - Multiples Forms and Regulation.- D The Physiological Effects of Adenosine and Adenine Nucleotides.- E Structure Activity Relationships at Adenosine and ATP Receptors.- F Effector Systems for Modulation of Biological Response by Purines.- G Phosphodiesterase Inhibitors - Mechanisms and Structure Activity Relationships.- Author Index.