Modification at C2 of myo‐inositol 1,4,5‐trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities

Robert A. Wilcox, Stephen T. Safrany, Dethard Lampe, Stephen J. Mills, Stefan R. Nahorski, Barry V.L. Potter

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44 Citations (Scopus)


Novel 2‐position‐modified d‐myo‐inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] analogues, dl‐2‐deoxy‐2‐fluoro‐myo‐inositol 1,4,5‐trisphosphate [dl‐2F‐Ins(1,4,5)P3], dl‐myo‐inositol 1,2,4,5‐tetrakisphosphate [dl‐Ins(1,2,4,5)P4], dl‐scyllo‐inositol 1,2,4‐trisphosphate [dl‐sc‐Ins(1,2,4)P3], scyllo‐inositol 1,2,4,5‐tetrakisphosphate [sc‐Ins(1,2,4,5)P4] and scyllo‐inositol 1,2,4,5‐tetrakisphos‐phorothioate [sc‐Ins(1,2,4,5)PS4] were investigated for their ability to bind to the Ins(1,4,5)P3 receptor, mobilise intracellular Ca2+ stores and interact with metabolic enzymes. With the exception of sc‐Ins(1,2,4,5)PS4, all the Ins(1,4,5)P3 analogues potently displaced [3H]Ins(1,4,5)P3 from its receptor in bovine adrenal cortex and were apparently potent full agonists at the Ca2+ mobilising Ins(1,4,5)P3 receptor of SH‐SY5Y cells, giving respective IC50 and EC50 values of: sc‐Ins(1,2,4,5)P4 (IC50 14 nM, EC50 77 nM), dl‐2F‐Ins(1,4,5)P3 (IC50 25 nM, EC50 105 nM), dl‐Ins(1,2,4,5)P4 (IC50 26 nM, EC50 163 nM), dl‐sc‐Ins(1,2,4)P3 (IC50 52 nM, EC50 171 nM), compared to Ins(1,4,5)P3 (IC50 4 nM, EC50 52 nM). sc‐Ins(1,2,4,5)P4 was equipotent to Ins(1,4,5)P3 for Ca2+ release making it the most potent inositol tetrakisphosphate and indeed Ins(1,4,5)P3 analogue yet characterised. In contrast, although sc‐Ins(1,2,4,5)PS4 (IC50 425 nM, EC50 1603 nM) was a significantly weaker ligand and agonist than Ins(1,4,5)P3, it was a partial agonist of high intrinsic activity with maximally effective concentrations releasing only about 80% of Ins(1,4,5)P3‐sensitive Ca2+ stores of SH‐SY5Y cells. Ins(1,4,5)P3 and sc‐Ins(1,2,4,5)P4 were readily metabolised by Ins(1,4,5)P3 3‐kinase and 5‐phosphatase activities, dl‐2F‐Ins(1,4,5)P3 and dl‐sc‐Ins(1,2,4)P3 were resistant to 5‐phosphatase, while sc‐Ins(1,2,4,5)PS4 and dl‐Ins(1,2,4,5)P4 were resistant to both 3‐kinase and 5‐phosphatase activity and were potent inhibitors of the 5‐phosphatase enzyme (Ki= 300 nM and 2.9 μM, respectively). These results demonstrate that modification of the 2‐position of Ins(1,4,5)P3, even with an anionic group, does not critically affect Ins(1,4,5)P3 receptor binding interaction or Ca2+ release, suggesting that the 2‐OH of Ins(1,4,5)P3 fails to interact significantly with the binding site of its receptor. However, modification remote from the crucial vicinal 4,5‐bisphosphate can affect analogue efficacy in Ca2+ release.

Original languageEnglish
Pages (from-to)115-124
Number of pages10
JournalEuropean Journal of Biochemistry
Issue number1
Publication statusPublished - Jul 1994
Externally publishedYes


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