Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are intracellular Ca2+ channels that are widely expressed in animal cells, where they mediate the release of Ca2+ from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP(3)Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca2+ release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP(3)R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca2+ release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP(3)Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.