Antiplatelet and antithrombotic activities of CP201, a newly synthesized 1,4-naphthoquinone derivative.
The antiplatelet and antithrombotic activities of a newly synthesized CP201, 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone on human platelet aggregation in vitro and murine pulmonary thrombosis in vivo were examined. In addition, the antiplatelet activity of CP201 involved in calcium-signaling cascade was also investigated. CP201 showed concentration-dependent inhibitory effects on platelet aggregation induced by collagen and thrombin, with IC50 values of 4.1+/-0.3 and 4.6+/-0.4 microM, respectively. Orally administered CP201 protected mice against the collagen plus epinephrine-induced thromboembolic death in a dose-dependent manner. On the other hand, CP201 did not alter such coagulation parameters as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in human plasma in vitro. These results suggest that the antithrombotic activity of CP201 may be due to antiplatelet rather than anticoagulation activity. CP201 potently inhibited platelet aggregation challenged by calcium ionophore A23187 and thapsigargin, which is a selective inhibitor of the Ca(2+)-ATPase pump, in a concentration-dependent manner, indicating that CP201 may have an inhibitory effect on calcium-signaling cascade. This was supported by measuring [Ca2+]i in platelets loaded with fura-3AM, where CP201 inhibited the rise in cytosolic Ca2+ mediated by thrombin. Taken together, these results suggest that CP201 may be a promising antithrombotic agent, and the antithrombotic effect of CP201 may be due to antiplatelet activity, which was mediated, at least partly, by the inhibition of cytosolic calcium mobilization.
Jin
Yong-Ri
YR
College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea.
Hwang
Kyung-Ae
KA
Cho
Mi-Ra
MR
Kim
Soo-Yeon
SY
Kim
Jin-Ho
JH
Ryu
Chung-Kyu
CK
Son
Dong-Ju
DJ
Park
Young-Hyun
YH
Yun
Yeo-Pyo
YP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011655:Pulmonary Embolism / Q000188:drug therapy
C489943:2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone; D005343:Fibrinolytic Agents; D009285:Naphthoquinones; D010975:Platelet Aggregation Inhibitors; C035342:1,4-naphthoquinone