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.
Riley, A. M., Correa, V., Mahon, M. F., Taylor, C. W., & Potter, B. V. L. (2001). Bicyclic analogues of D-myo-Inositol 1,4,5-trisphosphate related to adenophostin A: synthesis and biological activity. Journal of Medicinal Chemistry, 44(13), 2108-2117. https://doi.org/10.1021/jm0005499, https://doi.org/10.1021/jm0005499