Molecular Recognition at Adenine Nucleotide (P2) Receptors in Platelets
| Autor: | Liaman K. Mamedova, Kenneth A. Jacobson, Pedro Besada, Bhalchandra V. Joshi, Stefano Costanzi |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Blood Platelets
Models Molecular Agonist P2Y receptor Platelet Aggregation medicine.drug_class Immune receptor Biology Ligands Article Receptors Purinergic P2Y1 Structure-Activity Relationship Fibrinolytic Agents Adenine nucleotide medicine Humans Protease-activated receptor Receptor G protein-coupled receptor Molecular Structure Receptors Purinergic P2 Membrane Proteins Hematology Receptor antagonist Receptors Purinergic P2Y12 Adenosine Diphosphate Biochemistry Receptors Purinergic P2X Drug Design Cardiology and Cardiovascular Medicine Platelet Aggregation Inhibitors Signal Transduction |
| Zdroj: | Seminars in Thrombosis and Hemostasis. 31:205-216 |
| ISSN: | 1098-9064 0094-6176 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|