SYNTHETIC D-ENANTIOMER AND L-ENANTIOMER OF 2,2-DIFLUORO-2-DEOXY-MYO-INOSITOL 1,4,5-TRISPHOSPHATE INTERACT DIFFERENTLY WITH MYOINOSITOL 1,4,5-TRISPHOSPHATE BINDING-PROTEINS - IDENTIFICATION OF A POTENT SMALL MOLECULE 3-KINASE INHIBITOR

The ability of two enantiomeric fluoro-analogues Of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] to mobilize intracellular Ca2+ stores in SH-SY5Y neuroblastoma cells has been investigated. (-)-D-2,2-difluoro-2-deoxy-myo-Ins(1,4,5)P3 [D-2,2-F2-Ins(1,4,5)P3] was a full agonist [EC50 0.21 muM and slightly less potent than D-Ins(1,4,5)P3 [EC50 0.13 muM]. (+)-L-2,2-F2Ins(1,4,5)P3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P3 receptor. D-2,2-F2-Ins(1,4,5)P3 mobilized Ca2+ with broadly similar kinetics to Ins(1,4,5)P3 and was a substrate for Ins(1,4,5)P3 3-kinase inhibiting Ins(1,4,5)P3 phosphorylation (apparent K(i) = 10.2 muM but was recognised less well than Ins(1,4,5)P3. L-2,2-F2-Ins(1,4,5)P3 was a potent competitive inhibitor of 3-kinase (K(i) = 11.9 muM). Whereas D-2,2-F2-Ins(1,4,5)P3 was a good substrate for Ins(1,4,5)P3 5-phosphataSe, L-2,2-F2Ins(1,4,5)P3 was a relatively potent inhibitor (K(i) = 19.0 muM).