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Clustered disaccharide analogues of adenophostin A (2), i.e. mono-, di-, and tetravalent derivatives 6-8, respectively, were synthesized and evaluated as novel ligands for the tetrameric D-myo-inositol 1,4, 5-trisphosphate receptor (IP(3)R). The synthesis was accomplished via Sonogashira coupling of propargyl 2-O-acetyl-5-O-benzyl-3-O-(3, 4-di-O-acetyl-2, 6-di-O-benzyl-alpha-D-glucopyranosyl)-beta-D-ribofuranoside (16) with iodobenzene 18, 22, or 25, followed by deacetylation, phosphorylation, and deprotection. The abilities of the target compounds 6-8, as well as ribophostin 4, propylphostin 5, and IP(3) (1), to evoke Ca(2+) release from permeabilized hepatocytes or displacement of [(3)H]IP(3) from its receptor in hepatic membranes were compared. Although the binding affinities of 4-8 were similar, there were modest though significant differences in their potencies in Ca(2+) release assays: tetraphostin 8 > IP(3) approximately diphostin 7 > phenylphostin 6 > ribophostin 4 approximately propylphostin 5.

Type

Journal article

Journal

J Med Chem

Publication Date

24/08/2000

Volume

43

Pages

3295 - 3303

Keywords

Adenosine, Animals, Binding, Competitive, Calcium, Calcium Channels, Disaccharides, In Vitro Techniques, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Ligands, Liver, Male, Rats, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Sea Urchins, Structure-Activity Relationship