P2Y2 receptor ligands

The P2 nucleotide receptors are subdivided into a subfamily of ligand-gated ion channels (P2X receptors) activated by ATP and a family of GPCRs that consists of at least eight members including the P2Y₂ receptor which is expressed in epithelial cells, smooth-muscle cells, endothelial cells, leukocytes, osteoblast and cardiomyocytes. P2Y₂ receptors were found to be implicated in a variety of pathophysiological states such as lung diseases, cancer progression as well as vascular, inflammatory and immune diseases. Agonists could be interesting for the symptomatic treatment of cystic fibrosis and dry eye syndrome. The natural ligand UTP, as well as most reported analogs, are liable to enzymatic degradation at the surface of the air-ways. This results in a relative short time of action when these molecules are administered by inhalation.

Recently, we synthesized a UTP analogue (MRS2698) that combines a 2’-amino and a 2-thio modification. These modifications synergized to enhance potency and selectivity (EC₅₀ of 8 nM and 300-fold selectivity for P2Y₂ versus P2Y₄).

We’ re engaged to discover new P2Y2 receptor agonists with a high affinity and selectivity but also with an increased metabolic stability.

Researcher:

Collaborators: Ken Jacobson (Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, MD)