Agonists and antagonists for P2 receptors

摘要

Recent work has identified nucleotide agonists selective for P2Y_1, P2Y_2 and P2Y_6 receptors and nucleotide antagonists selective for P2Y_1, P2Y_(12) and P2X_1 receptors. Selective non-nucleotide antagonists have been reported for P2Y_1, P2Y_2, P2Y_6, P2Y_(12), P2Y_(13), P2Y_(2/3)/P2X_3 and P2X_7 receptors. For example, the dinucleotide INS 37217 (Up_4d C) potently activates the P2Y_2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2Y_(2/3)/P2X_3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y_(1,2,4,11) receptors, there is a preference for the North conformation as indicated with (N) -methanocarba analogues. The P2Y_1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC_(50) of 0.95 n M. MRS2365, an (i V)-methanocarba analogue of 2-Me SADP, displayed potency (EC_(50)) of 0.4n M at the P2Yt receptor, with >10 000-fold selectivity in comparison to P2Y_(12) and P2Y_(13) receptors. At P2Y_6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.