Structure-activity relationships of adenophostin A and related molecules at the 1-D-myo-inositol 1,4,5-trisphosphate receptor

D-myo-Inositol 1,4,5-trisphosphate [Ins(1,4,5)P,] is a well established, Ca2+-releasing, biological second messenger. Our aim has been to radically redesign the Ins(1,4,5)P3molecule to explore whether ring-contracted and carbohydrate-based mimics might be feasible targets for development of novel ligands for pharmacological intervention in the polyphosphoinositide pathway of cellular signaling. We have primarily employed two approaches: first, the use of carbohydrates as chiral starting materials for synthesis of cyclopentane-based Ins(1,4,5)P3mimics using ring-contraction methodologies; second, the design of mono- and disaccharide based polyphosphates both de novo and based upon the novel hyperagonist adenophostin A, which is more potent than the natural messenger itself, as novel Ins(1,4,5)P3receptor ligands. Our studies demonstrate that both approaches possess great potential to produce highly active mimics of this fundamental second messenger.