Takehara S, Mikashima H, Muramoto Y, Terasawa M, Setoguchi M, Tahara T
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Prostaglandins. 1990 Dec;40(6):571-83. doi: 10.1016/0090-6980(90)90002-d.
The inhibitory effect of Y-24180, 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-t hieno [3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine, on platelet activating factor (PAF)-induced platelet aggregation and the specific binding of 3H-PAF to platelets was compared with other thienodiazepine derivatives, WEB 2086 and etizolam. Y-24180 inhibited PAF-induced rabbit platelet aggregation in vitro (IC50 3.84 nM), but had little effect on adenosine diphosphate- or arachidonic acid-induced aggregation. WEB 2086 and etizolam also showed an inhibitory effect of PAF-induced aggregation (IC50 values are 456 and 6730 nM, respectively). In PAF-induced human platelet aggregation, Y-24180 (IC50 0.84 nM) was more potent than WEB 2086 (IC50 4.21 nM) and etizolam (IC50 998 nM). Y-24180, WEB 2086 and etizolam displaced 3H-PAF binding from the washed-platelets of rabbits with an IC50 value of 3.50, 9.35 and 29.5 nM, respectively. In rabbits, pretreatment with Y-24180 and WEB 2086 antagonized PAF-induced platelet aggregation dose-dependently. The significant inhibitory effect of Y-24180 (1 mg/kg, p.o.) lasted 72 hr after a single dose oral administration. WEB 2086 (10 mg/kg, p.o.) also antagonized the ex vivo response induced by PAF 1 hr after administration, but no significant effect was observed 3 hr after administration. Y-24180 displaced 3H-diazepam binding from the synaptosomal membranes of rat cerebral cortex with a Ki value of 3.68 microM. The affinity of Y-24180 for benzodiazepine(BZP) receptors was lower than those of WEB 2086 and etizolam and was about 1000 times lower than that for PAF receptors in platelets.
将Y-24180（4-(2-氯苯基)-2-[2-(4-异丁基苯基)乙基]-6,9-二甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓）对血小板活化因子（PAF）诱导的血小板聚集及3H-PAF与血小板特异性结合的抑制作用，与其他噻吩二氮杂卓衍生物WEB 2086和艾司唑仑进行了比较。Y-24180在体外抑制PAF诱导的兔血小板聚集（IC50为3.84 nM），但对二磷酸腺苷或花生四烯酸诱导的聚集作用很小。WEB 2086和艾司唑仑也显示出对PAF诱导聚集的抑制作用（IC50值分别为456和6730 nM）。在PAF诱导的人血小板聚集中，Y-24180（IC50为0.84 nM）比WEB 2086（IC50为4.21 nM）和艾司唑仑（IC50为998 nM）更有效。Y-24180、WEB 2086和艾司唑仑分别以3.50、9.35和29.5 nM的IC50值使3H-PAF从兔洗涤血小板上的结合发生位移。在兔中，用Y-24180和WEB 2086预处理可剂量依赖性地拮抗PAF诱导的血小板聚集。单次口服给药Y-24180（1 mg/kg）后，显著的抑制作用持续72小时。WEB 2086（10 mg/kg，口服）在给药后1小时也拮抗了PAF诱导的体内反应，但给药后3小时未观察到显著作用。Y-24180以3.68 microM的Ki值使3H-地西泮从大鼠大脑皮质突触体膜上的结合发生位移。Y-24180对苯二氮䓬（BZP）受体的亲和力低于WEB 2086和艾司唑仑，且比其对血小板中PAF受体的亲和力低约1000倍。
