Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y12 receptor when interacting with antagonists

Ding, Zhongren; Bynagari, Yamini Saraswathy; Mada, Sripal R.; Jakubowski, Joseph A.; Kunapuli, Satya P.

doi:10.1111/j.1538-7836.2008.03202.x

Cited by 36 publications

(26 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aggregation of human washed platelets in response to agonist or antagonists was analyzed using lumi-aggregometer (Model 400VS, Chrono-Log, Haverston, PA, USA) under stirring conditions (900 rpm) at 37°C as reported before [11], [12], [14], [15]. In some experiments, platelet secretion was monitored by measuring ATP release using CHRONO-LUME reagent in parallel with aggregation [11].…”

Section: Methodsmentioning

confidence: 99%

BF066, a Novel Dual Target Antiplatelet Agent without Significant Bleeding

Pan

Wei

et al. 2012

PLoS ONE

Self Cite

View full text Add to dashboard Cite

In this study, we report BF066, a novel adenine derivative, inhibits platelet activation and thrombosis via the adenosine receptor (A2A) activation and phosphodiesterase (PDE) inhibition. BF066 inhibits platelet aggregation and ATP releasing induced by multiple platelet agonists in a dose-dependent manner. The inhibition of BF066 on ADP-induced aggregation is potentiated by adenosine and can be dramatically antagonized by the A2A antagonist SCH58261. BF066 also inhibits the PDE activity and platelet spreading on fibrinogen. In FeCl3-injured mouse mesenteric arterial thrombosis model, BF066 prevents thrombus formation effectively, similar to clopidogrel. Intriguingly, at dose achieving similar antithrombotic effect compared to clopidogrel, BF066 does not increase bleeding significantly. Taken together, these results suggest that BF066 may be an effective and safe antiplatelet agent targeting both PDE and A2A. Considering the successful use of combined antiplatelet therapy, BF066 may be further developed as a novel dual target antiplatelet agent.

show abstract

Section: Methodsmentioning

confidence: 99%

BF066, a Novel Dual Target Antiplatelet Agent without Significant Bleeding

Pan

Wei

et al. 2012

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…The thienopyridine compounds ticlopidine ( 32 ), clopidogrel ( 33 , Savi et al, 2006), and prasugrel ( 34 , Sugidachi, Asai, Ogawa, Inoue, & Koike, 2000; Sugidachi, Mizuno, Ohno, Jakubowski, & Tomizawa, 2016) are liver‐activated prodrugs. Their active metabolites, such as R‐138727 (structure not shown, Dansette, Levent, Hessani, & Mansuy, 2015), have been shown to interact in an irreversible manner with the human P2Y 12 receptor protein (Algaier, Jakubowski, Asai, & von Kugelgen, 2008; Ding, Bynagari, Mada, Jakubowski, & Kunapuli, 2009; Savi et al, 2006; Zhang, Zhang, Gao, Zhang, et al, 2014). Competitive P2Y 12 receptor antagonists include the nucleotide derivatives cangrelor ( 35 , AR‐C69931MX, N 6 ‐(2‐methylthioethyl)‐2‐(3,3,3‐trifluoropropylthio)‐β,γ‐dichloromethylene‐ATP) and AR‐C67085 (2‐propylthio‐β,γ‐dichloromethylene‐D‐ATP, 28 ; Ingall et al, 1999) as well as nucleoside derivatives such as the orally active ticagrelor ( 36 , AZD6140, Springthorpe et al, 2007; Hoffmann et al, 2009; Hoffmann et al, 2014).…”

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

171

184

View full text Add to dashboard Cite

Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

show abstract

“…Residue C97 3.25 has been previously implicated by functional assays as a covalent binding site for the active metabolites of P2Y 12 R drugs 8,22 . Our aSEC results are consistent with C97 3.25 being the primary attachment site for the active metabolite of prasugrel, R-138727 (Extended Data Fig.…”

mentioning

confidence: 99%

Structure of the human P2Y12 receptor in complex with an antithrombotic drug

Zhang

Gao

et al. 2014

Nature

337

328

View full text Add to dashboard Cite

P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors1. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo2, which limits our under-standing of this receptor family. P2Y12R regulates platelet activation and thrombus formation3,4, and several antithrombotic drugs targeting P2Y12R—including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor—have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor)5,6 suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors7,8. Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.

show abstract

Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y12 receptor when interacting with antagonists

Cited by 36 publications

References 14 publications

BF066, a Novel Dual Target Antiplatelet Agent without Significant Bleeding

BF066, a Novel Dual Target Antiplatelet Agent without Significant Bleeding

Update of P2Y receptor pharmacology: IUPHAR Review 27

Structure of the human P2Y12 receptor in complex with an antithrombotic drug

Contact Info

Product

Resources

About