Effect of a potent cyclooxygenase inhibitor, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), on human platelets
Journal
Journal of Pharmacy and Pharmacology
Journal Volume
54
Journal Issue
7
Pages
967-974
Date Issued
2002
Author(s)
Abstract
Because the metabolites of arachidonic acid participate in many physiopathological responses, including inflammation and platelet aggregation, cyclooxygenase inhibitors are important in the treatment of associated diseases. A biologically active compound, 5-ethyl-4-methoxy-2-phenyl-quinoline (KTC-5), selectively and concentration dependently inhibited aggregation of platelets from man and ATP release caused by arachidonic acid (200 μM) and collagen (10 μg mL-1) without affecting the aggregation caused by thrombin (0.1 U mL-1) and U46619 (2 μM). The IC50 value (drug concentration inhibiting maximum response by 50%) of KTC-5 for aggregation induced by arachidonic acid and collagen was 0.11±0.04 μM and 0.20±0.03 μM, respectively. This inhibitory effect of KTC-5 was reversible and time dependent. KTC-5 specifically inhibited intracellular calcium mobilization initiated by arachidonic acid or collagen without affecting that caused by thrombin or U46619 in human platelets. Furthermore, KTC-5 inhibited thromboxane B2 and prostaglandin D2 formation provoked by arachidonic acid. The IC50 value of KTC-5 for arachidonic-acid-induced thromboxane B2 formation was 0.07±0.02 μM. Based on these observation, the data indicated that KTC-5 potently inhibited human platelet aggregation and ATP release mainly via the inhibition of the cyclooxygenase-1 activity. Moreover, KTC-5 inhibited lipopolysaccharide-induced prostaglandin E2 formation in RAW264.7 cells in the presence of external arachidonic acid with an IC50 value of 0.17±0.06 μM. Immunoblot analysis showed that KTC-5 did not affect the cyclooxygenase-2 expression in the presence of lipopolysaccharide on RAW264.7 cells. This result indicated that KTC-5 affects the activity of cyclooxygenase-2. According to these data, we concluded that KTC-5 is a cyclooxygenase inhibitor for both subtypes.
SDGs
Other Subjects
15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid; 5 ethyl 4 methoxy 2 phenylquinoline; adenosine triphosphate; arachidonic acid; calcium; collagen; cyclooxygenase 1; cyclooxygenase 2; imidazole; indometacin; ktc 5; lipopolysaccharide; prostaglandin D2; prostaglandin E2; prostaglandin synthase inhibitor; thrombin; thromboxane B2; unclassified drug; 5 ethyl 4 methoxy 2 phenylquinoline; 5-ethyl-4-methoxy-2-phenylquinoline; adenosine triphosphate; arachidonic acid; collagen; prostaglandin synthase inhibitor; quinoline derivative; animal cell; article; calcium cell level; calcium mobilization; cell line; concentration (parameters); concentration response; controlled study; dose time effect relation; drug effect; drug mechanism; drug potency; drug selectivity; drug specificity; enzyme activity; enzyme inhibition; human; human cell; IC 50; immunoblotting; inhibition kinetics; metabolic inhibition; mouse; nonhuman; peritoneum macrophage; protein determination; protein expression; protein synthesis inhibition; thrombocyte; thrombocyte aggregation inhibition; culture technique; enzymology; kinetics; secretion; thrombocyte; thrombocyte aggregation; Adenosine Triphosphate; Arachidonic Acid; Blood Platelets; Cell Culture Techniques; Collagen; Cyclooxygenase Inhibitors; Humans; Kinetics; Platelet Aggregation; Quinolines
Type
journal article