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, Ca 2+ -releasing, biological second messenger. Our aim has been to radically redesign the Ins(1,4,5)P 3 molecule 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)P 3 mimics 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)P 3 receptor ligands. Our studies demonstrate that both approaches possess great potential to produce highly active mimics of this fundamental second messenger.