P2Y Receptor

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Kenneth A Jacobson - One of the best experts on this subject based on the ideXlab platform.

  • caged agonist of P2Y1 and P2Y12 Receptors for light directed facilitation of platelet aggregation
    Biochemical Pharmacology, 2008
    Co-Authors: Zhanguo Gao, Christian Gachet, Beatrice Hechler, Pedro Besada, Kenneth A Jacobson
    Abstract:

    We have prepared a caged form (MRS2703) of a potent dual agonist of the P2Y(1) and P2Y(12) nucleotide Receptors, 2-MeSADP, by blocking the beta-phosphate group with a 1-(3,4-dimethyloxyphenyl)eth-1-yl phosphoester. Although MRS2703 is itself inactive at human P2Y(1) and P2Y(12) Receptors expressed heterologously in 1321N1 astrocytoma cells or in washed human platelets, this derivative readily regenerates the parent agonist upon mild irradiation with long-wave UV light (360 nm). The functional effect of the regenerated agonist was demonstrated by a rise in intracellular calcium mediated by either P2Y(1) or P2Y(12) Receptors in transfected cells. Washed human platelets exposed to a solution of MRS2703 were induced to aggregate upon UV irradiation. At 1.0 microM MRS2703, full aggregation was achieved within 1 min of irradiation. Thus, this caged nucleotide promises to be a useful probe for potent P2Y Receptor activation with light-directed spatial and temporal control.

  • international union of pharmacology lviii update on the P2Y g protein coupled nucleotide Receptors from molecular mechanisms and pathophysiology to therapy
    Pharmacological Reviews, 2006
    Co-Authors: Mariapia P. Abbracchio, Marta Fumagalli, Jean-marie Boeynaems, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Gillian E Knight, Eric A Barnard, Charles Kennedy, Kenneth A Jacobson
    Abstract:

    There have been many advances in our knowledge about different aspects of P2Y Receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More Receptor subtypes have been cloned and characterized and most orphan Receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y Receptor subtypes. More is known about the functional elements of the P2Y Receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y Receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y Receptors and Receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y Receptor subtypes in many different cell types are better understood and P2Y Receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

  • architecture of P2Y nucleotide Receptors structural comparison based on sequence analysis mutagenesis and homology modeling
    Journal of Medicinal Chemistry, 2004
    Co-Authors: Stefano Costanzi, Zhanguo Gao, Liaman K Mamedova, Kenneth A Jacobson
    Abstract:

    Human P2Y Receptors encompass at least eight subtypes of Class A G protein-coupled Receptors (GPCRs), responding to adenine and/or uracil nucleotides. Using a BLAST search against the Homo sapiens subset of the SWISS-PROT and TrEMBL databases, we identified 68 proteins showing high similarity to P2Y Receptors. To address the problem of low sequence identity between rhodopsin and the P2Y Receptors, we performed a multiple-sequence alignment of the retrieved proteins and the template bovine rhodopsin, combining manual identification of the transmembrane domains (TMs) with automatic techniques. The resulting phylogenetic tree delineated two distinct subgroups of P2Y Receptors: Gq-coupled subtypes (e.g., P2Y1) and those coupled to Gi (e.g., P2Y12). On the basis of sequence comparison we mutated three Tyr residues of the putative P2Y1 binding pocket to Ala and Phe and characterized pharmacologically the mutant Receptors expressed in COS-7 cells. The mutation of Y306 (7.35, site of a cationic residue in P2Y12) or Y203 in the second extracellular loop selectively decreased the affinity of the agonist 2-MeSADP, and the Y306F mutation also reduced antagonist (MRS2179) affinity by 5-fold. The Y273A (6.48) mutation precluded the Receptor activation without a major effect on the ligand-binding affinities, but the Y273F mutant Receptor still activated G proteins with full agonist affinity. Thus, we have identified new recognition elements to further define the P2Y1 binding site and related these to other P2Y Receptor subtypes. Following sequence-based secondary-structure prediction, we constructed complete models of all the human P2Y Receptors by homology to rhodopsin. Ligand docking on P2Y1 and P2Y12 Receptor models was guided by mutagenesis results, to identify the residues implicated in the binding process. Different sets of cationic residues in the two subgroups appeared to coordinate phosphate-bearing ligands. Within the P2Y1 subgroup these residues are R3.29, K/R6.55, and R7.39. Within the P2Y12 subgroup, the only residue in common with P2Y1 is R6.55, and the role of R3.29 in TM3 seems to be fulfilled by a Lys residue in EL2, whereas the R7.39 in TM7 seems to be substituted by K7.35. Thus, we have identified common and distinguishing features of P2Y Receptor structure and have proposed modes of ligand binding for the two representative subtypes that already have well-developed ligands.

  • 2 chloro n6 methyl n methanocarba 2 deoxyadenosine 3 5 bisphosphate is a selective high affinity P2Y1 Receptor antagonist
    British Journal of Pharmacology, 2002
    Co-Authors: José L. Boyer, Kenneth A Jacobson, Mary Adams, Gnana R Ravi, Kendall T Harden
    Abstract:

    We reported previously that bisphosphate derivatives of adenosine are antagonists of the P2Y1 Receptor and that modification of the ribose in these analogues is tolerated in the P2Y1 Receptor binding pharmacophore. Here we delineate the pharmacological activity of one such non-nucleotide molecule, 2-chloro N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate (MRS2279), in which the ribose is replaced by a cyclopentane ring constrained in the (N)-conformation by a cyclopropane moiety. MRS2279 antagonized 2MeSADP-stimulated inositol phosphate formation in turkey erythrocyte membranes with competitive kinetics (pKB=7.75). High affinity competitive antagonism by MRS2279 was also observed at the human P2Y1 Receptor (pKB=8.10) stably expressed in 1321N1 human astrocytoma cells. Antagonism was specific for the P2Y1 Receptor since MRS2279 had no effect on activation of the human P2Y2, P2Y4, P2Y6, or P2Y11 Receptors by their cognate agonists. MRS2279 also did not block the capacity of ADP to act through the Gi/adenylyl cyclase linked P2Y Receptor of platelets to inhibit cyclic AMP accumulation. In contrast, the P2Y1 Receptor is known to be obligatory in the process of ADP-induced platelet aggregation, and MRS2279 competitively inhibited ADP-promoted platelet aggregation with an apparent affnity (pKB=8.05) similar to that observed at the human P2Y1 Receptor heterologously expressed in 1321N1 cells. Taken together these results illustrate selective high affinity antagonism of the P2Y1 Receptor by a non-nucleotide molecule that should prove useful for pharmacological delineation of this Receptor in various tissues. Keywords: P2Y Receptors, P2Y1 Receptor antagonist, 2-chloro N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate, phospholipase C, adenylyl cyclase, platelet aggregation Introduction Appreciation of the importance of adenine and uridine nucleotides as extracellular signalling molecules has been heightened during the past decade by identification of up to 15 different mammalian Receptors for nucleotides (Fredholm et al., 1997; Ralevic & Burnstock, 1998). These Receptors are readily subdivided into the ligand-gated ion channel P2X Receptors and the G protein-coupled P2Y Receptors. The metabotropic P2Y Receptors are essentially ubiquitously expressed and regulate myriad physiological effects ranging from muscle contraction and epithelial cell Cl− secretion to immunological/inflammatory responses of circulating lymphocytes and platelet aggregation (Dubyak & El-Moatassim, 1993; Ralevic & Burnstock, 1998). Whereas a central role for extracellular nucleotides in many physiological effects is well-accepted, few nucleotide-regulated responses have been aligned unambiguously with a given P2 Receptor subtype. This follows from several problems associated with the study of nucleotide-regulated responses. First, a complex array of ectoenzymes hydrolyze and interconvert extracellular nucleotides (Zimmermann, 1996; Harden et al., 1997). Given that the P2Y Receptor subtypes are differentially activated by adenine and uridine tri- and diphosphates and selective stable agonists for these Receptors are not available, determination of P2Y Receptor identity in tissues using agonists alone has proven difficult. Second, few selective antagonists for the P2Y Receptors have been available, and many molecules utilized as antagonists to date not only block certain of the P2Y Receptors but also interact with P2X Receptors and many other proteins (Harden et al., 1995, 1998). Our laboratory has focused on the P2Y1 Receptor as a potentially important therapeutic target. This Receptor is relatively broadly distributed in the central nervous system and in peripheral tissues (Ralevic & Burnstock, 1998; Webb & Barnard, 1999), and its role in the platelet aggregation response to ADP has been a topic of increased interest (Leon et al., 1997, 1999; Jin et al., 1998; Hechler et al., 1998; Fabre et al., 1999). Our initial observation that adenosine bisphosphate molecules are competitive antagonists of the P2Y1 Receptor (Boyer et al., 1996a) has been followed by directed chemical syntheses of new molecules exhibiting potential as selective competitive antagonists of the P2Y1 Receptor (Camaioni et al., 1998; Kim et al., 2000). We recently reported the synthesis of a series of ribose-modified-2′-deoxyadenosine bisphosphate analogs (Nandanan et al., 2000). Fusion of a cyclopropane bridge into a cyclopentane ring indicated that a constrained carbocyclic ring was tolerated in place of the ribose moiety in molecules that retained relatively high affinity for the P2Y1 Receptor of turkey erythrocytes. We now report the pharmacological properties of the most promising of these molecules, 2-chloro-N6- methyl-(N)-methanocarba -2′-deoxyadenosine-3≈prime;,5′-bisphosphate (MRS2279). Our results reveal that a non-nucleotide bisphosphate molecule exhibits very high affinity and selectivity among the P2Y Receptors for the P2Y1 Receptor. This molecule does not bind to the Gi/adenylyl cyclase-linked P2Y Receptor of platelets, and therefore, can be utilized as a high affinity probe for differentiating the role of the P2Y1 Receptor versus a similar Receptor for ADP found in platelets and other tissues.

  • acyclic analogues of deoxyadenosine 3 5 bisphosphates as P2Y1 Receptor antagonists
    Journal of Medicinal Chemistry, 2000
    Co-Authors: Carola Gallorodriguez, José L. Boyer, T K Harden, Mary Adams, S Y Jang, E Nandanan, Kenneth A Jacobson
    Abstract:

    P2Y1 Receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y Receptor ligands. Specifically, the binding site of the P2Y1 Receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospho...

Geoffrey Burnstock - One of the best experts on this subject based on the ideXlab platform.

  • P2Y Receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • P2Y Receptors version 2019 4 in the iuphar bps guide to pharmacology database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • international union of pharmacology lviii update on the P2Y g protein coupled nucleotide Receptors from molecular mechanisms and pathophysiology to therapy
    Pharmacological Reviews, 2006
    Co-Authors: Mariapia P. Abbracchio, Marta Fumagalli, Jean-marie Boeynaems, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Gillian E Knight, Eric A Barnard, Charles Kennedy, Kenneth A Jacobson
    Abstract:

    There have been many advances in our knowledge about different aspects of P2Y Receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More Receptor subtypes have been cloned and characterized and most orphan Receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y Receptor subtypes. More is known about the functional elements of the P2Y Receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y Receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y Receptors and Receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y Receptor subtypes in many different cell types are better understood and P2Y Receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

  • Purine- and pyrimidine-induced responses and P2Y Receptor characterization in the hamster proximal urethra
    BRIT J PHARMACOL, 2005
    Co-Authors: Geoffrey Burnstock
    Abstract:

    1 Purine and pyrimidine compounds were investigated on hamster proximal urethral circular smooth muscle preparations. In situ hybridization studies were carried out to localize P2Y(1), P2Y(2), P2Y(4) and P2Y(6) mRNA. Protein expression was studied using Western blotting analysis with antibodies against P2Y(1) and P2Y(2) Receptors.2 The hamster urethra relaxed with an agonist potency order of: 2-MeSADP > beta,gamma-meATP = ATP adenosine = ADP > 2- MeSATP > alpha,beta-meATP > TTP > CTP = UTP > GTP = UDP. The high potency of 2- MeSADP is suggestive of an action via P2Y(1) Receptors. Although the order is not characteristic for any known single P2Y Receptor subtype, it may represent a combination of P2Y Receptor subtypes.3 The selective P2Y(1) Receptor antagonist MRS2179 inhibited ATP-, 2-MeSADP-, 2-MeSATP-, beta,gamma-meATP-, andto a lesser degree alpha,beta-meATP-induced responses.4 Adenosine, but not ATP, was inhibited by the adenosine Receptor antagonist 8-phenyltheophylline, indicating that ATP was not acting via adenosine following enzymatic breakdown.5 Western blotting analysis showed the expression of both P2Y(1) and P2Y(2) Receptors, confirming the results obtained with in situ hybridization that showed the expression of both P2Y(1) and P2Y(2), but not P2Y(4) or P2Y(6) mRNA, in smooth muscle layers of the hamster proximal urethra.6 It is proposed that the relaxant response of the urethra to ATP may be evoked through the activation of the combination of Receptors for P2Y(1) andto a lesser extent P2Y(2) Receptors, which may mediate a trophic effect in addition. A P2Y subtype responsive to alpha,beta-meATP and P1 Receptors may contribute to urethral smooth muscle relaxation.

  • purinergic signalling to rat ovarian smooth muscle changes in p2x Receptor expression during pregnancy
    Cells Tissues Organs, 2004
    Co-Authors: Harshini Katugampola, Geoffrey Burnstock
    Abstract:

    The expression of P2X and P2Y Receptor subtypes in the smooth muscle of the rat ovary during the oestrus cycle and pregnancy was examined using immunohistochemistry. RT-PCR studies of P2X Receptor mRN

Peter Illes - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of NMDA Receptor Current in Layer V Pyramidal Neurons of the Rat Prefrontal Cortex by P2Y Receptor Activation
    2007
    Co-Authors: Kerstin Wirkner, Marco Weber, Segundo J. Guzman, Thomas Krause, Jochen Fuchs, Laszlo Ko Les, Wolfgang No Renberg, Peter Illes
    Abstract:

    Current responses to N-methyl-D-aspartate (NMDA) in layer V pyramidal neurons of the rat prefrontal cortex were potentiated by the P2 Receptor agonists adenosine 59-triphosphate (ATP) and uridine 59-triphosphate (UTP). The failure of these nucleotides to induce inward current on fast local superfusion suggested the activation of P2Y rather than P2X Receptors. The potentiation by ATP persisted in a Ca 21-free superfusion medium but was abolished by 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N9,N9tetraacetic acid tetrakis(acetoxymethyl) ester, cyclopiazonic acid, 7-nitroindazole, fluoroacetic acid, bafilomycin, and tetanus toxin, indicating that an astrocytic signaling molecule may participate. Because the metabotropic glutamate Receptor (mGluR) agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) (group I/II) and (RS)-3,5-dihydroxyphenylglycine (group I) both imitated the effect of ATP and the group I mGluR antagonist 1-aminoindan

  • modulation of nmda Receptor current in layer v pyramidal neurons of the rat prefrontal cortex by P2Y Receptor activation
    Cerebral Cortex, 2006
    Co-Authors: Kerstin Wirkner, Marco Weber, Segundo J. Guzman, Thomas Krause, Jochen Fuchs, Albrecht Gunther, Laszlo Koles, Wolfgang Norenberg, Peter Illes
    Abstract:

    Current responses to N-methyl-D-aspartate (NMDA) in layer V pyramidal neurons of the rat prefrontal cortex were potentiated by the P2 Receptor agonists adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP). The failure of these nucleotides to induce inward current on fast local superfusion suggested the activation of P2Y rather than P2X Receptors. The potentiation by ATP persisted in a Ca(2+)-free superfusion medium but was abolished by 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester, cyclopiazonic acid, 7-nitroindazole, fluoroacetic acid, bafilomycin, and tetanus toxin, indicating that an astrocytic signaling molecule may participate. Because the metabotropic glutamate Receptor (mGluR) agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) (group I/II) and (RS)-3,5-dihydroxyphenylglycine (group I) both imitated the effect of ATP and the group I mGluR antagonist 1-aminoindan-1,5-dicarboxylic acid or a combination of selective mGluR(1) (7-(hydroxyimino)-cyclopropa[b]chromen-1a-carboxylate) and mGluR(5) (2-methyl-6-(phenylethynyl)pyridine) antagonists abolished the facilitation by ATP, it was concluded that the signaling molecule may be glutamate. Pharmacological tools known to interfere with the transduction cascade of type I mGluRs (guanosine 5'-O-(3-thiodiphosphate), U-73122, xestospongin C, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, calmodulin kinase II [CAMKII] inhibitor peptide) depressed the actions of both ATP and ACPD. Characterization of the P2Y Receptor by agonists (ATP and UTP), antagonists (suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid), and knockout mice (P2Y(2)(-/-)) suggested that the nucleotides act at the P2Y(4) subtype. In conclusion, we propose that exogenous and probably also endogenous ATP release vesicular glutamate from astrocytes by P2Y(4) Receptor activation. This glutamate then stimulates type I mGluRs of layer V pyramidal neurons and via the G(q)/phospholipase C/inositol 1,4,5-trisphosphate/Ca(2+)/CAMKII transduction pathway facilitates NMDA Receptor currents.

  • adenine nucleotides inhibit recombinant n type calcium channels via g protein coupled mechanisms in hek 293 cells involvement of the P2Y13 Receptor type
    British Journal of Pharmacology, 2004
    Co-Authors: Kerstin Wirkner, Joana Schweigel, Zoltan Gerevich, Heike Franke, Clemens Allgaier, Edward Leon Barsoumian, Henning J Draheim, Peter Illes
    Abstract:

    1. N-type Ca(2+) channel modulation by an endogenous P2Y Receptor was investigated by the whole-cell patch-clamp method in HEK 293 cells transfected with the functional rabbit N-type calcium channel. 2. The current responses (I(Ca(N))) to depolarizing voltage steps were depressed by ATP in a concentration-dependent manner. Inclusion of either guanosine 5'-O-(3-thiodiphosphate) or pertussis toxin into the pipette solution as well as a strongly depolarizing prepulse abolished the inhibitory action of ATP. 3. In order to identify the P2Y Receptor subtype responsible for this effect, several preferential agonists and antagonists were studied. Whereas the concentration-response curves of ADP and adenosine 5'-O-(2-thiodiphosphate) indicated a higher potency of these agonists than that of ATP, alpha,beta-methylene ATP, UTP and UDP were considerably less active. The effect of ATP was abolished by the P2Y Receptor antagonists suramin and N(6)-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP, but not by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, 2'deoxy-N(6)-methyladenosine-3',5'-diphosphate or 2-methylthio AMP. 4. Using reverse transcription and polymerase chain reaction, mRNA for the P2Y(1), P2Y(4), P2Y(6), P2Y(11) and P2Y(13) Receptor subtypes, but not the P2Y(2), and P2Y(12) subtypes, was detected in HEK 293 cells. 5. Immunocytochemistry confirmed the presence of P2Y(1), and to a minor extent that of P2Y(4), but not of P2Y(2) Receptors. 6. Hence, it is tempting to speculate that P2Y(13) Receptors may inhibit N-type Ca(2+) channels via the betagamma subunits of the activated G(i) protein.

Jean-marie Boeynaems - One of the best experts on this subject based on the ideXlab platform.

  • P2Y Receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • P2Y Receptors version 2019 4 in the iuphar bps guide to pharmacology database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • bone phenotypes of p2 Receptor knockout mice
    Frontiers in Bioscience, 2011
    Co-Authors: Isabel R Orriss, Susanne Syberg, Ning Wang, Bernard Robaye, Alison Gartland, Niklas Rye Jorgensen, Timothy R Arnett, Jean-marie Boeynaems
    Abstract:

    The action of extracellular nucleotides is mediated by ionotropic P2X Receptors and G-protein coupled P2Y Receptors. The human genome contains 7 P2X and 8 P2Y Receptor genes. Knockout mice strains are available for most of them. As their phenotypic analysis is progressing, bone abnormalities have been observed in an impressive number of these mice: distinct abnormalities in P2X7-/- mice, depending on the gene targeting construct and the genetic background, decreased bone mass in P2Y1-/- mice, increased bone mass in P2Y2-/- mice, decreased bone resorption in P2Y6-/- mice, decreased bone formation and bone resorption in P2Y13-/- mice. These findings demonstrate the unexpected importance of extracellular nucleotide signalling in the regulation of bone metabolism via multiple P2 Receptors and distinct mechanisms involving both osteoblasts and osteoclasts.

  • international union of pharmacology lviii update on the P2Y g protein coupled nucleotide Receptors from molecular mechanisms and pathophysiology to therapy
    Pharmacological Reviews, 2006
    Co-Authors: Mariapia P. Abbracchio, Marta Fumagalli, Jean-marie Boeynaems, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Gillian E Knight, Eric A Barnard, Charles Kennedy, Kenneth A Jacobson
    Abstract:

    There have been many advances in our knowledge about different aspects of P2Y Receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More Receptor subtypes have been cloned and characterized and most orphan Receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y Receptor subtypes. More is known about the functional elements of the P2Y Receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y Receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y Receptors and Receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y Receptor subtypes in many different cell types are better understood and P2Y Receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

  • Cloning of a human purinergic P2Y Receptor coupled to phospholipase C and adenylyl cyclase.
    The Journal of biological chemistry, 1997
    Co-Authors: Didier Communi, Cédric Govaerts, Marc Parmentier, Jean-marie Boeynaems
    Abstract:

    Clones encoding a new human P2Y Receptor, provisionally called P2Y11, have been isolated from human placenta complementary DNA and genomic DNA libraries. The 1113-base pair open reading frame is interrupted by one intron. The P2Y11 Receptor is characterized by considerably larger second and third extracellular loops than the subtypes described so far. The deduced amino acid sequence exhibits 33% amino acid identity with the P2Y1 Receptor, its closest homolog. Northern blot analysis detected human P2Y11 Receptor messenger RNA in spleen and HL-60 cells. The level of P2Y11 transcripts was strongly increased in these cells after granulocyte differentiation induced by retinoic acid or dimethyl sulfoxide. The new Receptor was stably expressed in 1321N1 astrocytoma and CHO-K1 cells, where it couples to the stimulation of both the phosphoinositide and adenylyl cyclase pathways, a unique feature among the P2Y family. The rank order of agonists potency was: ATP > 2-methylthio-ATP >>> ADP, whereas UTP and UDP were inactive, indicating that it behaves as a selective purinoceptor.

José L. Boyer - One of the best experts on this subject based on the ideXlab platform.

  • P2Y Receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • P2Y Receptors version 2019 4 in the iuphar bps guide to pharmacology database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Mariapia P. Abbracchio, Stefania Ceruti, Rebecca Hills, Marta Fumagalli, Jean-marie Boeynaems, R. G. Humphries, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Kazu Inoue
    Abstract:

    P2Y Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned Receptors to endogenously expressed Receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y Receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these Receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 Receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 Receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

  • international union of pharmacology lviii update on the P2Y g protein coupled nucleotide Receptors from molecular mechanisms and pathophysiology to therapy
    Pharmacological Reviews, 2006
    Co-Authors: Mariapia P. Abbracchio, Marta Fumagalli, Jean-marie Boeynaems, Christian Gachet, José L. Boyer, Geoffrey Burnstock, Gillian E Knight, Eric A Barnard, Charles Kennedy, Kenneth A Jacobson
    Abstract:

    There have been many advances in our knowledge about different aspects of P2Y Receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More Receptor subtypes have been cloned and characterized and most orphan Receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y Receptor subtypes. More is known about the functional elements of the P2Y Receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y Receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y Receptors and Receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y Receptor subtypes in many different cell types are better understood and P2Y Receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

  • 2 chloro n6 methyl n methanocarba 2 deoxyadenosine 3 5 bisphosphate is a selective high affinity P2Y1 Receptor antagonist
    British Journal of Pharmacology, 2002
    Co-Authors: José L. Boyer, Kenneth A Jacobson, Mary Adams, Gnana R Ravi, Kendall T Harden
    Abstract:

    We reported previously that bisphosphate derivatives of adenosine are antagonists of the P2Y1 Receptor and that modification of the ribose in these analogues is tolerated in the P2Y1 Receptor binding pharmacophore. Here we delineate the pharmacological activity of one such non-nucleotide molecule, 2-chloro N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate (MRS2279), in which the ribose is replaced by a cyclopentane ring constrained in the (N)-conformation by a cyclopropane moiety. MRS2279 antagonized 2MeSADP-stimulated inositol phosphate formation in turkey erythrocyte membranes with competitive kinetics (pKB=7.75). High affinity competitive antagonism by MRS2279 was also observed at the human P2Y1 Receptor (pKB=8.10) stably expressed in 1321N1 human astrocytoma cells. Antagonism was specific for the P2Y1 Receptor since MRS2279 had no effect on activation of the human P2Y2, P2Y4, P2Y6, or P2Y11 Receptors by their cognate agonists. MRS2279 also did not block the capacity of ADP to act through the Gi/adenylyl cyclase linked P2Y Receptor of platelets to inhibit cyclic AMP accumulation. In contrast, the P2Y1 Receptor is known to be obligatory in the process of ADP-induced platelet aggregation, and MRS2279 competitively inhibited ADP-promoted platelet aggregation with an apparent affnity (pKB=8.05) similar to that observed at the human P2Y1 Receptor heterologously expressed in 1321N1 cells. Taken together these results illustrate selective high affinity antagonism of the P2Y1 Receptor by a non-nucleotide molecule that should prove useful for pharmacological delineation of this Receptor in various tissues. Keywords: P2Y Receptors, P2Y1 Receptor antagonist, 2-chloro N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate, phospholipase C, adenylyl cyclase, platelet aggregation Introduction Appreciation of the importance of adenine and uridine nucleotides as extracellular signalling molecules has been heightened during the past decade by identification of up to 15 different mammalian Receptors for nucleotides (Fredholm et al., 1997; Ralevic & Burnstock, 1998). These Receptors are readily subdivided into the ligand-gated ion channel P2X Receptors and the G protein-coupled P2Y Receptors. The metabotropic P2Y Receptors are essentially ubiquitously expressed and regulate myriad physiological effects ranging from muscle contraction and epithelial cell Cl− secretion to immunological/inflammatory responses of circulating lymphocytes and platelet aggregation (Dubyak & El-Moatassim, 1993; Ralevic & Burnstock, 1998). Whereas a central role for extracellular nucleotides in many physiological effects is well-accepted, few nucleotide-regulated responses have been aligned unambiguously with a given P2 Receptor subtype. This follows from several problems associated with the study of nucleotide-regulated responses. First, a complex array of ectoenzymes hydrolyze and interconvert extracellular nucleotides (Zimmermann, 1996; Harden et al., 1997). Given that the P2Y Receptor subtypes are differentially activated by adenine and uridine tri- and diphosphates and selective stable agonists for these Receptors are not available, determination of P2Y Receptor identity in tissues using agonists alone has proven difficult. Second, few selective antagonists for the P2Y Receptors have been available, and many molecules utilized as antagonists to date not only block certain of the P2Y Receptors but also interact with P2X Receptors and many other proteins (Harden et al., 1995, 1998). Our laboratory has focused on the P2Y1 Receptor as a potentially important therapeutic target. This Receptor is relatively broadly distributed in the central nervous system and in peripheral tissues (Ralevic & Burnstock, 1998; Webb & Barnard, 1999), and its role in the platelet aggregation response to ADP has been a topic of increased interest (Leon et al., 1997, 1999; Jin et al., 1998; Hechler et al., 1998; Fabre et al., 1999). Our initial observation that adenosine bisphosphate molecules are competitive antagonists of the P2Y1 Receptor (Boyer et al., 1996a) has been followed by directed chemical syntheses of new molecules exhibiting potential as selective competitive antagonists of the P2Y1 Receptor (Camaioni et al., 1998; Kim et al., 2000). We recently reported the synthesis of a series of ribose-modified-2′-deoxyadenosine bisphosphate analogs (Nandanan et al., 2000). Fusion of a cyclopropane bridge into a cyclopentane ring indicated that a constrained carbocyclic ring was tolerated in place of the ribose moiety in molecules that retained relatively high affinity for the P2Y1 Receptor of turkey erythrocytes. We now report the pharmacological properties of the most promising of these molecules, 2-chloro-N6- methyl-(N)-methanocarba -2′-deoxyadenosine-3≈prime;,5′-bisphosphate (MRS2279). Our results reveal that a non-nucleotide bisphosphate molecule exhibits very high affinity and selectivity among the P2Y Receptors for the P2Y1 Receptor. This molecule does not bind to the Gi/adenylyl cyclase-linked P2Y Receptor of platelets, and therefore, can be utilized as a high affinity probe for differentiating the role of the P2Y1 Receptor versus a similar Receptor for ADP found in platelets and other tissues.

  • acyclic analogues of deoxyadenosine 3 5 bisphosphates as P2Y1 Receptor antagonists
    Journal of Medicinal Chemistry, 2000
    Co-Authors: Carola Gallorodriguez, José L. Boyer, T K Harden, Mary Adams, S Y Jang, E Nandanan, Kenneth A Jacobson
    Abstract:

    P2Y1 Receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y Receptor ligands. Specifically, the binding site of the P2Y1 Receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospho...