Antiplatelet mechanisms of TA-993 and its metabolite MB3 in ADP-induced platelet aggregation.
We investigated the antiplatelet mechanisms of TA-993 [(-)-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one maleate] and its metabolite MB3 (deacetyl and N-monomethyl TA-993) in human platelets stimulated by ADP in vitro. TA-993 and MB3 concentration-dependently inhibited fibrinogen binding to the ADP-stimulated platelets as well as inhibiting platelet aggregation. The antiplatelet effect of MB3 was about 300 times more potent than those of TA-993 and a glycoprotein IIb/IIIa receptor antagonist, Arg-Gly-Asp-Ser (RGDS). Aggregation of ADP-treated fixed platelets caused by the addition of fibrinogen was inhibited by RGDS but not by TA-993 and MB3. TA-993 and MB3 inhibited ADP-induced polymerization of actin filaments. Neither TA-993 nor MB3 affected cyclic AMP and cyclic GMP levels in resting platelets, and nor suppressed the increase in intracellular Ca(2+) concentration induced by ADP. These results suggest that the antiplatelet mechanisms of TA-993 and MB3 may involve inactivation of glycoprotein IIb/IIIa receptors via inhibition of the polymerization of actin.
Katoh
M
M
Discovery Research Laboratories, Tanabe Seiyaku, Co., Ltd., 2-2-50 Kawagishi, Toda-shi, 335-8505, Saitama, Japan. katoh-m@tanabe.co.jp
Karasawa
T
T
Doi
H
H
Odawara
A
A
Takagi
M
M
Ikeo
T
T
Narita
H
H
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology; D016257:Fura-2; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
D000199:Actins; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; C097363:TA 993; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C046617:arginyl-glycyl-aspartyl-serine; D000242:Cyclic AMP; D004110:Diltiazem; D006152:Cyclic GMP; D002118:Calcium; D016257:Fura-2