Structure–activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors

Shaver, Sammy R.; Rideout, Janet L.; Pendergast, William; Douglass, James G.; Brown, E. G.; Boyer, José L.; Patel, Roshni I.; Redick, Catherine C.; Jones, Arthur C.; Picher, Maryse; Yerxa, Benjamin R.

doi:10.1007/s11302-005-0648-2

Cited by 86 publications

(141 citation statements)

References 28 publications

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“…This occurred despite a fall in GFR and suggested that proximal tubular reabsorption was markedly reduced [353]. Ap 4 A can stimulate a number of P2 receptor subtypes, including P2Y 1 and P2Y 4 receptors [331,410], which are both expressed in the rat proximal tubule (P2Y 1 apically, P2Y 4 basolaterally); intravenous delivery of the agonist does not allow differentiation between these possibilities.…”

Section: Renal Tubulesmentioning

confidence: 96%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

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Section: Renal Tubulesmentioning

confidence: 96%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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“…INS45973 is an agonist of P2Y2/P2Y4 receptors, while INS415 is an agonist of P2Y2/ P2Y6 receptors. 19 …”

Section: Reagentsmentioning

confidence: 99%

The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration

Rossi

Manfredini

Bertolini

et al. 2006

Blood

103

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“…Abbreviations: AR-C67085MX, 2-(propylthio)-β,γ-dichloromethylene-ATP; MRS2179, N 6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate; RB2, Reactive blue 2. Note: Ap 4 A also activates various P2X receptors and the rat P2Y 4 receptor (Wildman et al 2003), but not the human P2Y 4 receptor (Shaver et al 2005). Suramin is known to inhibit G proteins and other intracellular targets.…”

Section: Figmentioning

confidence: 99%

Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

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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

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Structure–activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors

Cited by 86 publications

References 28 publications

Purinergic signalling in the kidney in health and disease

Purinergic signalling in the kidney in health and disease

The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration

Agonists and Antagonists for P2 Receptors

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