Photoaffinity analogue for the anti-inflammatory drug alpha-trinositol: synthesis and identification of putative molecular targets.
Avainsanat
Abstrakti
alpha-Trinositol (alpha T), or Ins(1,2,6)P3, is a semisynthetic inositol trisphosphate produced commercially by the partial degradation of phytic acid with phytase. The molecular targets mediating the mechanism of action of this novel anti-inflammatory, analgesic, and antivasoconstrictive drug are unknown. A new photoaffinity analogue, 4-[3H]BZDC-alpha T, has been prepared in which the [3H]-p-benzoyldihydrocinnamoyl ([3H]BZDC) photophore is tethered through an O-(5-aminopentanoyl) linkage to the 4-OH of alpha T. Photoaffinity labeling experiments with two human tissues, umbilical cord vascular smooth muscle cells and platelet membranes, revealed proteins that were selectively labeled by 4-[3H]BZDC-alpha T. Thus, co-incubation with alpha T but not with Ins(1,3,4,5)P4 during photolysis competitively displaced labeling of a 55 kDa platelet protein. In vascular epithelial cells, alpha T and Ins(1,3,4,5)P4 both displaced labeling of a 55 and 43 kDa proteins. The identification of putative protein targets for alpha T in smooth vascular tissue may have important implications in elucidation of the mechanism of action of this unusual drug.