title: G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions.
abstract: The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic structures of both agonist- and antagonist-bound forms of the A(2A)AR have provided unprecedented three-dimensional detail concerning molecular recognition in the binding site and the conformational changes in receptor activation. It is apparent that this ubiquitous cell signaling system has implications for understanding and treating many diseases. ATP and other nucleotides are readily released from intracellular sources under conditions of injury and organ stress, such as hypoxia, ischemia, or mechanical stress, and through channels and vesicular release. Adenosine may be generated extracellularly or by cellular release. Therefore, depending on pathophysiological factors, in a given tissue, there is often a tonic activation of one or more of the ARs or P2YRs that can be modulated by exogenous agents for a beneficial effect. Thus, this field has provided fertile ground for pharmaceutical development, leading to clinical trials of selective receptor ligands as imaging agents or for conditions including cardiac arrhythmias, ischemia/reperfusion injury, diabetes, pain, thrombosis, Parkinson's disease, rheumatoid arthritis, psoriasis, dry eye disease, pulmonary diseases such as cystic fibrosis, glaucoma, cancer, chronic hepatitis C, and other diseases.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. kajacobs@helix.nih.gov
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2