Recently, activation of the P2Y12 G-protein coupled receptor (GPCRs) has been shown to be central to platelet aggregation. Drugs preventing platelet aggregation are being tested, but one that would be specific to the P2Y12 receptor would capture a large market share. Developing drugs for the P1Y12 receptor is difficult, because it is a receptor that is naturally activated by ADP. Since practically every cell expresses ADP-activatable receptors, developing a drug screening program directed specifically at the P2Y12 receptor has not been possible.
University of California, Irvine researchers have discovered that the P1Y12 receptor can be activated by a specific natural ligand, ADP-glucose, and that upon activation the receptor transduces a G-protein coupled intracellular signal. Researchers have also identified this receptor's immunogenic peptides. These immunogenic peptides can be used to induce antibodies to the receptor and they can be used in assays to isolate ADP-glucose receptor ligands, agonists, or antagonists. Researchers have also found that signaling through the ADP-glucose receptor leads to potent effects on smooth muscle contractile responses.
A screen for P2Y12 using ADP-glucose has been developed. This assay monitors the P2Y12 receptor reactivity in a high-throughput format and thus will lead to the identification of antagonists and/or agonists that are specific to the P2Y12 receptor. Antagonists will mainly target platelet aggregation. Agonists and antagonists might also be used in the treatment of gastrointestinal disorders (e.g. inflammatory bowel disease) that require modulation of smooth muscle contractility. P2Y12 receptor signaling also induces vasorelaxation. Antagonists and agonists can be used to modulate vascular smooth muscle function by acting as vasoconstrictors or vasodilators with applications to cardiovascular disorders. A diagnostic may also be developed using the antibodies to assay for normal ADP-glucose cell function.
Other areas involving smooth muscle contractility dysfunction that may benefit from ADP-glucose receptor signaling include allergic, inflammatory, respiratory, infectious, autoimmune, psychiatric, and metabolic disorders.
|United States Of America||Issued Patent||6,790,608||09/14/2004||2001-001|