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Molecular Pharmacology

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Research ArticleArticle

Structural Analogues ofd-myo-Inositol-1,4,5-trisphosphate and Adenophostin A: Recognition by Cerebellar and Platelet Inositol-1,4,5-trisphosphate Receptors

C. T. Murphy, A. M. Riley, C. J. Lindley, D. J. Jenkins, J. Westwick and B. V. L. Potter
Molecular Pharmacology October 1997, 52 (4) 741-748; DOI: https://doi.org/10.1124/mol.52.4.741
C. T. Murphy
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A. M. Riley
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C. J. Lindley
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D. J. Jenkins
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J. Westwick
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B. V. L. Potter
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Abstract

Adenophostins A and B, which are metabolic products of the fungusPenicillium brevicompactum, are potent agonists at thed-myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. In the current study, adenophostin A was ∼50-fold more potent than Ins(1,4,5)P3at both releasing Ca2+ from the intracellular stores of permeabilized platelets and displacing [3H]Ins(1,4,5)P3 from its receptor on rat cerebellar membranes. Various analogues bearing structural features found in the adenophostins and/or Ins(1,4,5)P3 were examined to elucidate the molecular basis for the observed enhanced potency. 2-AMP did not induce Ca2+ release from permeabilized platelets or have any effect on Ins(1,4,5)P3-induced Ca2+ release. Two carbohydrate-based analogues, (2-hydroxyethyl)-α-d-glucopyranoside-2′,3,4-trisphosphate and α,α′-trehalose-3,4,3′,4′-tetrakisphosphate, could induce release of Ca2+ and displace [3H]Ins(1,4,5)P3 from its binding site on rat cerebellar membranes, although both were less potent than Ins(1,4,5)P3. In common with adenophostin A, release of Ca2+ from the intracellular stores could be inhibited by heparin, and both analogues were metabolically resistant. This study is the first to demonstrate the activity of a synthetic disaccharide at the Ins(1,4,5)P3 receptor and that the Ins(1,4,5)P3 receptor is capable of accommodating an increased steric bulk. The minimal importance of the 2-hydroxyl group of Ins(1,4,5)P3 (occupied by the pyranoside oxygen in adenophostin) was confirmed by comparing the activity ofdl-scyllo-Ins(1,2,4)P3 [which differs from Ins(1,4,5)P3 solely by the orientation of this hydroxyl group] with that of Ins(1,4,5)P3. An analogue of this compound, namely,dl-6-CH2OH-scyllo-Ins(1,2,4)P3, which possesses an equatorial hydroxymethyl group analogous to the 5′-hydroxymethyl group of adenophostin, was found to be equipotent to Ins(1,4,5)P3, demonstrating the tolerance of the Ins(1,4,5)P3 receptor to additional steric bulk at this position.

Footnotes

    • Received March 28, 1997.
    • Accepted June 20, 1997.
  • Send reprint requests to: Dr. C. T. Murphy, Department of Pharmacology, School of Pharmacy & Pharmacology, University of Bath, Bath, Avon BA2 7AY, United Kingdom. E-mail:c.t.murphy{at}bath.ac.uk

  • This work was supported by the British Heart Foundation (J.W., C.T.M.) and The Wellcome Trust with project (J.W., B.V.L.P.) and program grant (BVLP) support and the Biotechnology and Biological Research Council, Intracellular Signaling Programme (B.V.L.P.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (4)
Molecular Pharmacology
Vol. 52, Issue 4
1 Oct 1997
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Research ArticleArticle

Structural Analogues ofd-myo-Inositol-1,4,5-trisphosphate and Adenophostin A: Recognition by Cerebellar and Platelet Inositol-1,4,5-trisphosphate Receptors

C. T. Murphy, A. M. Riley, C. J. Lindley, D. J. Jenkins, J. Westwick and B. V. L. Potter
Molecular Pharmacology October 1, 1997, 52 (4) 741-748; DOI: https://doi.org/10.1124/mol.52.4.741

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Research ArticleArticle

Structural Analogues ofd-myo-Inositol-1,4,5-trisphosphate and Adenophostin A: Recognition by Cerebellar and Platelet Inositol-1,4,5-trisphosphate Receptors

C. T. Murphy, A. M. Riley, C. J. Lindley, D. J. Jenkins, J. Westwick and B. V. L. Potter
Molecular Pharmacology October 1, 1997, 52 (4) 741-748; DOI: https://doi.org/10.1124/mol.52.4.741
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