Bicyclic analogues of D-myo-Inositol 1,4,5-trisphosphate related to adenophostin A: synthesis and biological activity

Andrew M. Riley, Vanessa Correa, Mary F. Mahon, Colin W. Taylor, Barry V. L. Potter

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The high affinity of adenophostin A for 1D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] receptors may be related to an alteration in the position of its 2'-phosphate group relative to the corresponding 1-phosphate group in Ins(1,4,5)P-3. To investigate this possibility, two bicyclic trisphosphates 9 and 10, designed to explore the effect of relocating the l-phosphate group of Ins(1,4,5)P-3 using a novel fused-ring system, were synthesized from myo-inositol. Biological evaluation of 9 and 10 at the Ins(1,4,5)P-3 receptors of hepatocytes showed that both were recognized by hepatic Ins(1,4,5)P-3 receptors and both stimulated release of Ca2+ from intracellular stores, but they had lower affinity than Ins(1,4,5)P-3. This finding may be explained by considering the three-dimensional structures of 9 and 10 in light of recent studies on the conformation of adenophostin A.
Original languageEnglish
Pages (from-to)2108-2117
Number of pages10
JournalJournal of Medicinal Chemistry
Volume44
Issue number13
DOIs
Publication statusPublished - 2001

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