Antiplatelet Mechanism of 2-Chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an Antithrombotic Agent

Abstract

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.

Inhibitory Effects of J78, a Newly Synthesized 1,4-Naphthoquinone Derivative, on Experimental Thrombosis and Platelet Aggregation

“…It has been reported that several compounds with the backbone of 1,4-naphthoquinone chemical structure possess antiplatelet activities [13][14][15][16]. We have also previously reported that some 1,4-naphthoquinone derivatives possessed antiplatelet and antithrombotic effects [17][18][19][20][21]. These results indicate that this congener compound may be a new source in the antiplatelet and antithrombotic drug development.…”

“…It has been reported that NTP, a synthesized 1,4-naphthoquinone derivative, inhibited platelet aggregation by decreasing [Ca 2+ ] i elevation [16]. In our previous studies, some 1,4-naphthoquinone derivatives also inhibited platelet aggregation by inhibition of Ca 2+ mobilization [20,21]. Thus, it was not unreasonable to hypothesize that the antiplatelet activities of J78 may partly relate to its inhibition of Ca 2+ mobilization at least.…”

“…It has been reported that NTP, 2-p-mercapto-phenyl-1,4-naphthoquinone, inhibited thromboxane A 2 production [16]. In our previous studies, several 1,4-naphthoquinone derivatives also displayed their antiplatelet activity by the inhibition of TXA 2 formation [19,21].…”