Both D- and L-Glucose Polyphosphates Mimic D-myo-Inositol 1,4,5-Trisphosphate: New Synthetic Agonists and Partial Agonists at the Ins(1,4,5)P₃ Receptor

Chiral sugar derivatives are potential cyclitol surrogates of the Ca2+-mobilizing intracellular messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3]. Six novel polyphosphorylated analogues derived from both D- and L-glucose were synthesized. Binding to Ins(1,4,5)P-3 receptors [Ins(1,4,5)P3R] and the ability to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P(3)Rs were investigated. beta-D-Glucopyranosyl 1,3,4-tris-phosphate, with similar phosphate regiochemistry and stereochemistry to Ins(1,4,5)P-3, and alpha-D-glucopyranosyl 1,3,4-tris-phosphate are full agonists, being equipotent and 23-fold less potent than Ins(1,4,5)P-3, respectively, in Ca2+-release assays and similar to Ins(1,4,5)P-3 and 15-fold weaker in binding assays. They can be viewed as truncated analogues of adenophostin A and refine understanding of structure-activity relationships for this Ins(1,4,5)P3R agonist. L-Glucose-derived ligands, methyl alpha-L-glucopyranoside 2,3,6-trisphosphate and methyl alpha-L-glucopyranoside 2,4,6-trisphosphate, are also active, while their corresponding D-enantiomers, methyl alpha-D-glucopyranoside 2,3,6-trisphosphate and methyl alpha-D-glucopyranoside 2,4,6-trisphosphate, are inactive. Interestingly, both L-glucose-derived ligands are partial agonists: they are among the least efficacious agonists of Ins(1,4,5)P3R yet identified, providing new leads for antagonist development.