Synthesis and P2Y receptor activity of nucleoside 5'-phosphonate derivatives

Bioorg Med Chem Lett. 2009 Jun 1;19(11):3002-5. doi: 10.1016/j.bmcl.2009.04.027. Epub 2009 Apr 14.

Abstract

Ribose-based nucleoside 5'-diphosphates and triphosphates and related nucleotides were compared in their potency at the P2Y receptors with the corresponding nucleoside 5'-phosphonate derivatives. Phosphonate derivatives of UTP and ATP activated the P2Y(2) receptor but were inactive or weakly active at P2Y(4) receptor. Uridine 5'-(diphospho)phosphonate was approximately as potent at the P2Y(2) receptor as at the UDP-activated P2Y(6) receptor. These results suggest that removal of the 5'-oxygen atom from nucleotide agonist derivatives reduces but does not prevent interaction with the P2Y(2) receptor. Uridine 5'-(phospho)phosphonate as well as the 5'-methylenephosphonate equivalent of UMP were inactive at the P2Y(4) receptor and exhibited maximal effects at the P2Y(2) receptor that were 50% of that of UTP suggesting novel action of these analogues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / chemical synthesis
  • Adenosine Diphosphate / chemistry
  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / chemical synthesis
  • Adenosine Triphosphate / chemistry
  • Cell Line, Tumor
  • Humans
  • Nucleotides / chemical synthesis*
  • Nucleotides / chemistry
  • Purinergic P2 Receptor Agonists*
  • Receptors, Purinergic P2 / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / metabolism
  • Uridine Diphosphate / analogs & derivatives
  • Uridine Diphosphate / chemical synthesis
  • Uridine Diphosphate / chemistry
  • Uridine Triphosphate / analogs & derivatives
  • Uridine Triphosphate / chemical synthesis
  • Uridine Triphosphate / chemistry

Substances

  • Nucleotides
  • Purinergic P2 Receptor Agonists
  • Receptors, Purinergic P2
  • Recombinant Proteins
  • Uridine Diphosphate
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Uridine Triphosphate