Bisphosphonate Derivatives of 2’-C-Methyl-, and 3’-C-Methyl-Adenosine as Ligands at P2Y1 and P2Y2 Receptors

The P2 purinergic receptors are a major class of receptors in the human body activated by nucleotides, such as ATP, ADP, UTP or UDP. They are subdivided into G protein-coupled or metabotropic P2 receptors (GPCRs), designated P2Y, and ligand-gated ion channels or ionotropic receptors, termed P2X. Both families constitute important drug targets due to their involvement in the modulation of various functions in many tissues and organs under both normal and pathophysiological conditions. The P2Y receptors are expressed in most human tissues including the heart, placenta, vascular endothelia, prostate, ovary, platelets and brain (1). Until recently, the only P2Y receptor ligands in pharmaceutical use are the antithrombotic P2Y12 receptor antagonists Clopidogrel, Ticagrelor, Ticlopidine and Prasugrel. Therefore, there is a growing effort to identify new agents to act at the P2Y receptors for pharmaceutical development. Recently, we have synthesized the 2’- and 3’-C-methyl derivatives of ADP and evaluated their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of phospholipase C (PLC) at recombinant human receptors expressed in atrocytoma cells. From the functional assay 2’-C-methyl-ADP resulted a full agonist at P2Y1 receptor, while 3’-C-methyl-ADP acted as partial agonist at P2Y2 receptor. The interesting biological activity of these compounds is limited by the presence of the pyrophosphate bridge in the structure, which is highly sensitive to both enzymatic and chemical hydrolysis. It is thus of outmost interest to prepare stable analogues of these nucleotides. Hence, bisphosphonate derivatives of 2’-C-methyl- and 3’-C-methyl-adenosine were synthesized and tested at hP2Y1 and hP2Y2 receptors. The results of the functional assay will be discussed.