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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.
Shipton, Megan L; Riley, Andrew M; Rossi, Ana M; Brearley, Charles A; Taylor, Colin W; Potter, Barry V L.
Affiliation
  • Shipton ML; Drug Discovery & Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U. K.
  • Riley AM; Drug Discovery & Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U. K.
  • Rossi AM; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U. K.
  • Brearley CA; School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, U. K.
  • Taylor CW; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U. K.
  • Potter BVL; Drug Discovery & Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U. K.
J Med Chem ; 63(10): 5442-5457, 2020 05 28.
Article in En | MEDLINE | ID: mdl-32286062
ABSTRACT
Chiral sugar derivatives are potential cyclitol surrogates of the Ca2+-mobilizing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Six novel polyphosphorylated analogues derived from both d- and l-glucose were synthesized. Binding to Ins(1,4,5)P3 receptors [Ins(1,4,5)P3R] and the ability to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P3Rs were investigated. ß-d-Glucopyranosyl 1,3,4-tris-phosphate, with similar phosphate regiochemistry and stereochemistry to Ins(1,4,5)P3, and α-d-glucopyranosyl 1,3,4-tris-phosphate are full agonists, being equipotent and 23-fold less potent than Ins(1,4,5)P3, respectively, in Ca2+-release assays and similar to Ins(1,4,5)P3 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 α-l-glucopyranoside 2,3,6-trisphosphate and methyl α-l-glucopyranoside 2,4,6-trisphosphate, are also active, while their corresponding d-enantiomers, methyl α-d-glucopyranoside 2,3,6-trisphosphate and methyl α-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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Polyphosphates / Inositol 1,4,5-Trisphosphate / Molecular Mimicry / Inositol 1,4,5-Trisphosphate Receptors / Drug Partial Agonism / Glucose Limits: Animals / Humans Language: En Year: 2020 Type: Article

Full text: 1 Database: MEDLINE Main subject: Polyphosphates / Inositol 1,4,5-Trisphosphate / Molecular Mimicry / Inositol 1,4,5-Trisphosphate Receptors / Drug Partial Agonism / Glucose Limits: Animals / Humans Language: En Year: 2020 Type: Article