Agonists and Antagonists for P2 Receptors

Abstract

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 , P2X 2/3 /P2X 3 and P2X 7 receptors. For example, the dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X 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 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC 50 ) of 0.4 nM at the P2Y 1 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. Extracellular purine and pyrimidine nucleotides act as neurotransmitters/modulators . These ubiquitous signalling molecules modulate the function of diverse mammalian cell types and tissues under both normal and pathophysiological conditions. Receptors for extracellular nucleotides have been characterized through medicinal chemical, molecular biological, and pharmacological approaches. The eight subtypes of P2Y receptors, denoted P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 , are all seven transmembrane-spanning (7TM) receptors, which couple to G proteins. The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the

P2X7receptors mediate deleterious renal epithelial-fibroblast cross talk

“…Third and finally, overexpression of the P2X 7 receptor enhanced necrotic RPTC supernatant-induced death of NRK-49F. Although P2Y1 is also expressed in renal fibroblasts in the normal kidney, pretreatment with MRS-2500, a selective P2Y1 inhibitor (19), did not interfere with the death of renal fibroblasts in response to necrotic RPTC, suggesting that this receptor does not mediate renal fibroblast death.…”

“…5, A and B, treatment with suramin and PPAD significantly reduced necrotic RPTC supernatant-induced death of NRK-49F at 50 and 100 M, respectively. However, treatment with MRS-2500 did not improve cell survival of NRK-49F in the range of doses from 10 to 200 nM that was reported to effectively inhibit P2Y receptors (19) (Fig. 5C).…”

“…To determine whether P2 receptors mediate death of renal interstitial fibroblasts following exposure to necrotic RPTC and if so, to identify which class is responsible, we examined the effect of suramin, PPADS, and MRS-2500 on the viability of NRK-49F. Suramin is a general P2 inhibitor (14); PPADS is a selective inhibitor of P2X receptors (14); and MRS-2500 is a selective inhibitor of P2Y receptors (19). As shown in Fig.…”

P2X Receptors as Drug Targets

“…2) and the corresponding di-and monophosphate derivatives represent the first nanomolar antagonists at P2X1, P2X3, and P2X2/3 subtypes . TNP-ATP is several orders of magnitude less potent at P2X4, P2X5, and P2X7 Jacobson et al, 2006;Jarvis, 2010). TNP-ATP is rapidly metabolized, which limits its utility as a functional P2X3 receptor antagonist (Lewis et al, 1998;Donnelly-Roberts et al, 2008).…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…P2X receptors have been explored as therapeutic targets, e.g., for chronic inflammatory diseases and pain. In particular, P2X3 and P2X7 receptor antagonists have been developed and exhibited antinociceptive or antiinflammatory activity in animal models of these diseases [152].…”