Synthesis and P2Y receptor activity of nucleoside 5'-phosphonate derivatives.
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.
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Ghent, Belgium.
Liesbet
L
Cosyn
Serge
S
Van Calenbergh
Bhalchandra V
BV
Joshi
Hyojin
H
Ko
Rhonda L
RL
Carter
T
T
Kendall Harden
Kenneth A
KA
Jacobson
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D006801:Humans; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D014530:Uridine Diphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
D009711:Nucleotides; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D011994:Recombinant Proteins; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate