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Molecular Recognition at Adenine Nucleotide (P2) Receptors in Platelets
| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Jacobson, Kenneth A. Mamedova, Liaman Joshi, Bhalchandra V. Besada, Pedro Costanzi, Stefano |
| Description | Country affiliation: United States Author Affiliation: Jacobson KA ( Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA. kajacobs@helix.nih.gov) |
| 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)-methano-carba 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 α,β-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. |
| File Format | HTM / HTML |
| ISSN | 00946176 |
| e-ISSN | 10989064 |
| Journal | Seminars in Thrombosis and Hemostasis |
| Issue Number | 2 |
| Volume Number | 31 |
| Language | English |
| Publisher | Thieme |
| Publisher Date | 2005-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Vascular Diseases Discipline Hematology Adenosine Diphosphate Physiology Blood Platelets Drug Effects Platelet Aggregation Receptors, Purinergic P2 Drug Design Fibrinolytic Agents Chemistry Pharmacology Therapeutic Use Ligands Membrane Proteins Models, Molecular Molecular Structure Platelet Aggregation Inhibitors Classification Receptors, Purinergic P2x Receptors, Purinergic P2y1 Receptors, Purinergic P2y12 Signal Transduction Structure-activity Relationship Research Support, U.s. Gov't, P.h.s. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Hematology Cardiology and Cardiovascular Medicine |
