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 P2Y2 receptor but were inactive or weakly active at P2Y4 receptor. Uridine 5′-(diphospho)phosphonate was approximately as potent at the P2Y2 receptor as at the UDP-activated P2Y6 receptor. These results suggest that removal of the 5′-oxygen atom from nucleotide agonist derivatives reduces but does not prevent interaction with the P2Y2 receptor. Uridine 5′-(phospho)phosphonate as well as the 5′-methylenephosphonate equivalent of UMP were inactive at the P2Y4 receptor and exhibited maximal effects at the P2Y2 receptor that were ⩽50% of that of UTP suggesting novel action of these analogues.