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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 1-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 Ca(2+) 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.

Type

Journal article

Journal

J Med Chem

Publication Date

21/06/2001

Volume

44

Pages

2108 - 2117

Keywords

Adenosine, Animals, Calcium, Calcium Channel Agonists, Chromatography, Thin Layer, Crystallography, X-Ray, Hepatocytes, In Vitro Techniques, Indicators and Reagents, Inositol 1,4,5-Trisphosphate, Kinetics, Liver, Membranes, Models, Molecular, Molecular Conformation, Rats, Spectrophotometry, Ultraviolet, Stereoisomerism