Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-α-threofuranosyl ring systems: interactions with P2Y receptors Original Research Article

The ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of the P2Y1 receptor has been successfully substituted with a rigid methanocarba ring system, leading to the conclusion that the North (N) ring conformation is preferred in receptor binding. Similarly, at P2Y2 and P2Y4 receptors, nucleotides constrained in the (N) conformation interact equipotently with the corresponding ribosides. We now have synthesized and examined as P2Y receptor ligands nucleotide analogues substituted with two novel ring systems: (1) a (N) locked-carbocyclic (cLNA) derivative containing the oxabicyclo[2.2.1]heptane ring system and (2) l-α-threofuranosyl derivatives. We have also compared potencies and preferred conformations of these nucleotides with the known anhydrohexitol-containing P2Y1 receptor antagonist MRS2283. A cLNA bisphosphate derivative MRS2584 21 displayed a Ki value of 22.5 nM in binding to the human P2Y1 receptor, and antagonized the stimulation of PLC by the potent P2Y1 receptor agonist 2-methylthio-ADP (30 nM) with an IC50 of 650 nM. The parent cLNA nucleoside bound only weakly to an adenosine receptor (A3). Thus, this ring system afforded some P2Y receptor selectivity. A l-α-threofuranosyl bisphosphate derivative 9 displayed an IC50 of 15.3 μM for inhibition of 2-methylthio-ADP-stimulated PLC activity. l-α-Threofuranosyl-UTP 13 was a P2Y receptor agonist with a preference for P2Y2 (EC50 = 9.9 μM) versus P2Y4 receptors. The P2Y1 receptor binding modes, including rotational angles, were estimated using molecular modeling and receptor docking.