RT Journal Article
SR Electronic
T1 <em>myo</em>-Inositol 1,4,6-Trisphosphorothioate and<em>myo</em>-Inositol 1,3,6-Trisphosphorothioate: Partial Agonists with Very Low Intrinsic Activity at the Platelet<em>myo</em>-Inositol 1,4,5-Trisphosphate Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 595
OP 601
DO 10.1124/mol.57.3.595
VO 57
IS 3
A1 Christine T. Murphy
A1 Andrew M. Riley
A1 Steve J. Mills
A1 Catherine J. Lindley
A1 Barry V. L. Potter
A1 John Westwick
YR 2000
UL http://molpharm.aspetjournals.org/content/57/3/595.abstract
AB Racemic mixtures and enantiomerically pure d-isomers of both myo-inositol 1,3,6-trisphosphorothioate [Ins(1,3,6)PS3] and myo-inositol 1,4,6-trisphosphorothioate [Ins(1,4,6)PS3], prepared by total synthesis, were examined in Ca2+ flux and binding assays. Both d-Ins(1,3,6)PS3 andd-Ins(1,4,6)PS3 were shown to be low intrinsic activity partial agonists at the platelet myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor, releasing less than 20% of the Ins(1,4,5)P3-sensitive Ca2+ store. d-Ins(1,4,6)PS3displaced specifically bound [3H]Ins(1,4,5)P3from rat cerebellar membranes, although displacement was some 34-fold weaker than by d-Ins(1,4,5)P3.d-Ins(1,4,6)PS3 displaced [3H]Ins(1,4,5)P3 from cerebellar membranes with roughly twice the affinity ofdl-Ins(1,4,6)PS3 (IC50 value = 1.4 ± 0.35 μM compared with 2.15 ± 0.13 μM), whereasd-Ins(1,3,6)PS3 displaced [3H]Ins(1,4,5)P3 with roughly twice the affinity of dl-Ins(1,3,6)PS3 (IC50value = 17.5 ± 5.8 μM compared with 34 ± 10 μM), confirming that the activity of both these phosphorothioates resides in their d-enantiomers. Increasing concentrations of either d-Ins(1,3,6)PS3 ord-Ins(1,4,6)PS3 were able to partially antagonize Ca2+ release induced by submaximal concentrations of Ins(1,4,5)P3, an inhibition that could be overcome by increasing the concentration of Ins(1,4,5)P3, suggesting competition for binding at the Ins(1,4,5)P3-R. The only low-efficacy partial agonists at the Ins(1,4,5)P3-R discovered to date have been phosphorothioates; the novel d-Ins(1,3,6)PS3and d-Ins(1,4,6)PS3 can now be added to this small group of analogs. However,d-Ins(1,4,6)PS3 has a relatively high affinity for the Ins(1,4,5)P3-R but maintains the lowest efficacy of all the partial agonists thus far identified. As such, it may be a useful tool for pharmacological intervention in the polyphosphoinositide pathway and an important lead compound for the development of further Ins(1,4,5)P3-R antagonists.