Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors.
Org Biomol Chem
; 14(8): 2504-14, 2016 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-26818818
ABSTRACT
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca(2+) channels that are widely expressed in animal cells, where they mediate the release of Ca(2+) from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca(2+) release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca(2+) release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Inositol 1,4,5-Trifosfato
/
Fosfatos de Inositol
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article