Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and L-alpha-threofuranosyl ring systems: interactions with P2Y receptors

The ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) 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 P2Y(2) and P2Y(4) receptors, nucleotides constrained in the (N) conformation interact equipolently 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-alpha-threofuranosyl derivatives. We have also compared potencies and preferred conformations of these nucleotides with the known anhydrohexitol-containing P2Y(1) receptor antagonist MRS2283. A cLNA bisphosphate derivative MRS2584 21 displayed a K-i value of 22.5 nM in binding to the human P2Y 1 receptor, and antagonized the stimulation of PLC by the potent P2Y, receptor agonist 2-methylthio-ADP (30 nM) with an IC50 of 650 nM. The parent cLNA nucleoside bound only weakly to an adenosine receptor (A(3)) Thus, this ring system afforded some P2Y receptor selectivity. A L-a-threofuranosyl bisphosphate derivative 9 displayed an IC50 of 15.3 muM for inhibition of 2-methylthio-ADP-stimulated PLC activity. L-alpha-Threofuranosyl-UTP 13 was a P2Y receptor agonist with a preference for P2Y(2) (EC50 = 9.9 muM) versus P2Y(4) receptors. The P2Y(1) receptor binding modes, including rotational angles, were estimated using molecular modeling and receptor docking. (C) 2004 Elsevier Ltd. All rights reserved.