title: Molecular recognition at adenine nucleotide (P2) receptors in platelets.
abstract: Transmembrane signaling through P2Y receptors for extracellular nucleotides controls a diverse array of cellular processes, including thrombosis. Selective agonists and antagonists of the two P2Y receptors present on the platelet surface-the G (q)-coupled P2Y (1) subtype and the G (i)-coupled P2Y (12) subtype-are now known. High-affinity antagonists of each have been developed from nucleotide structures. The (N)-methanocarba bisphosphate derivatives MRS2279 and MRS2500 are potent and selective P2Y (1) receptor antagonists. The carbocyclic nucleoside AZD6140 is an uncharged, orally active P2Y (12) receptor antagonist of nM affinity. Another nucleotide receptor on the platelet surface, the P2X (1) receptor, the activation of which may also be proaggregatory, especially under conditions of high shear stress, has high-affinity ligands, although high selectivity has not yet been achieved. Although alpha,beta-methylene-adenosine triphosphate (ATP) is the classic agonist for the P2X (1) receptor, where it causes rapid desensitization, the agonist BzATP is among the most potent in activating this subtype. The aromatic sulfonates NF279 and NF449 are potent antagonists of the P2X (1) receptor. The structures of the two platelet P2Y receptors have been modeled, based on a rhodopsin template, to explain the basis for nucleotide recognition within the putative transmembrane binding sites. The P2Y (1) receptor model, especially, has been exploited in the design and optimization of antagonists targeted to interact selectively with that subtype.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA. kajacobs@helix.nih.gov
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Liaman
authors.initials: L
authors.lastname: Mamedova
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Pedro
authors.initials: P
authors.lastname: Besada
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D005343:Fibrinolytic Agents; D008024:Ligands; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate