Antiplatelet mechanism of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent.
The effects of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin-, arachidonic acid- and thapsigargin-induced aggregation of washed human platelets with the IC50 values of 22.2+/-0.7, 6.5+/-0.2, and 7.6+/-0.1 microM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate-conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen-glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin-induced increase in intracellular Ca2+ mobilization at the dose of 30 microM and ATP secretion in a dose-dependent manner. It also inhibited thrombin- and arachidonic acid-induced thromboxane A2 formation in human platelet dose-dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A2 formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.
Zhang
Y H
YH
College of Pharmacy, Chungbuk National University, Heungduk-Gu, Cheongju, Korea.
Chung
K H
KH
Ryu
C K
CK
Lee
Y H
YH
Kim
T J
TJ
Song
Y S
YS
Hwang
K A
KA
Yun
Y P
YP
D000255:Adenosine Triphosphate / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis
D009285:Naphthoquinones; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D005340:Fibrinogen; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D013917:Thrombin; D016650:Fluorescein-5-isothiocyanate; C407362:NQ304; D002118:Calcium