Journal article
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
- Abstract:
- Chiral sugar derivatives are potential cyclitol surrogates in 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 abilities to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P3Rs were investigated. β-D-Glucopyranosyl 1,3,4-trisphosphate, with similar phosphate regiochemistry and stereo-chemistry to Ins(1,4,5)P3 and α-D-glucopyranosyl 1,3,4-trisphosphate 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 structure-activity relationship understanding 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 amongst the least efficacious agonists of Ins(1,4,5)P3R yet identified, providing new leads for antagonist development.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Accepted manuscript, 1.8MB, Terms of use)
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- Publisher copy:
- 10.1021/acs.jmedchem.0c00215
Authors
- Publisher:
- American Chemical Society
- Journal:
- Journal of Medicinal Chemistry More from this journal
- Volume:
- 63
- Issue:
- 10
- Pages:
- 5442–5457
- Publication date:
- 2020-04-14
- Acceptance date:
- 2020-04-14
- DOI:
- EISSN:
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1520-4804
- ISSN:
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0022-2623
- Language:
-
English
- Keywords:
- Pubs id:
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1100166
- Local pid:
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pubs:1100166
- Deposit date:
-
2020-04-15
Terms of use
- Copyright holder:
- American Chemical Society
- Copyright date:
- 2020
- Rights statement:
- © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties
- Notes:
- This is the accepted manuscript version of the article. The final version is available from ACS Publications at: https://doi.org/10.1021/acs.jmedchem.0c00215
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