P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions including platelet aggregation, smooth muscle cell proliferation and immune regulation. The P2Y receptors belong to the GPCR superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date there have only been a limited number of small molecule P2Y receptor antagonists that have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation.
The
human P2Y2 receptor (hP2Y2R)
is a G-protein-coupled receptor that shows promise as a therapeutic
target for many important conditions, including for antimetastatic
cancer and more recently for idiopathic pulmonary fibrosis. As such,
there is a need for new hP2Y2R antagonists
and molecular probes to study this receptor. Herein, we report the
development of a new series of non-nucleotide hP2Y2R antagonists, based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1),
leading to the discovery of a series of fluorescent ligands containing
different linkers and fluorophores. One of these conjugates, 98, displayed micromolar affinity for hP2Y2R (pKd = 6.32 ± 0.10, n = 17) in a bioluminescence-energy-transfer (BRET) assay.
Confocal microscopy with this ligand revealed displaceable membrane
labeling of astrocytoma cells expressing untagged hP2Y2R. These properties make 98 one of the
first tools for studying hP2Y2R distribution
and organization.
Abstract5-Fluoroanthranilic acid (FAA)-resistant mutants were selected in homothallic diploids of three Saccharomyces species, taking care to isolate mutants of independent origin. Mutations were assigned to complementation groups by interspecific complementation with S. cerevisiae tester strains. In all three species, trp3, trp4 and trp5 mutants were recovered. trp1 mutants were also recovered if the selection was imposed on a haploid strain. Thus, FAA selection may be more generally applicable than was previously described.
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