title: R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet.
abstract: R 59 022 (6-[2-[4-[(4-fluorophenyl) phenylmethylene)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-alpha] pyrimidin-5-one) was found to inhibit diacylglycerol kinase in human red blood cell membranes at concentrations where polyphosphoinositide phosphodiesterase, phosphatidylinositol kinase, and phosphatidylinositol 4-phosphate kinase activity remained unaffected. The concentration needed for half-maximal inhibition (IC50) was 2.8 +/- 1.5 X 10(-6) M for the kinase acting on endogenous diacylglycerol and 3.3 +/- 0.4 X 10(-6) M when 1-oleoyl-2-acetylglycerol (OAG) was added exogenously as substrate. In intact platelets, R 59 022 inhibits the phosphorylation of OAG to 1-oleoyl-2-acetylglyceryl-3-phosphoric acid (OAPA) (IC50: 3.8 +/- 1.2 X 10(-6) M); concomitantly the stimulation of protein kinase C activity by OAG was amplified. When in platelets inositol lipid turnover is accelerated by thrombin, further addition of R 59 022 results in a marked elevation of diacylglycerol levels, a decreased formation of phosphatidic acid and an increased protein kinase C activity as compared with the controls. It is concluded that in studies on the signal-transducing system coupled to inositol lipid metabolism R 59 022 might occupy a role comparable to cyclic AMP phosphodiesterase inhibitors, since it potentiates the effect of the putative second messenger diacylglycerol by preventing its rapid metabolism.
mesh_terms: D001792:Blood Platelets / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D019852:Diacylglycerol Kinase; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004910:Erythrocyte Membrane / Q000378:metabolism; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008970:Molecular Weight; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011188:Potassium / Q000378:metabolism; D011493:Protein Kinase C / Q000097:blood*; D011744:Pyrimidinones / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D004075:Diglycerides; D005989:Glycerides; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D011744:Pyrimidinones; D013844:Thiazoles; C038237:1-oleoyl-2-acetylglycerol; C047505:R 59022; D012964:Sodium; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D013917:Thrombin; D008274:Magnesium; D011188:Potassium; D002118:Calcium