کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5827145 | 1558919 | 2015 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
In vitro pharmacological characterization of vorapaxar, a novel platelet thrombin receptor antagonist
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کلمات کلیدی
PAR1FLIPRμMPrPVorapaxarEGTAPAR1 antagonistMgCl2NaClK2HPO4CaCl2KClHClkoffBSA - BSADMSO - DMSObovine serum albumin - آلبومین سرم گاوMyocardial infarction - آنفارکتوس میوکاردethylene glycol tetraacetic acid - اتیلن گلیکول تتراستیک اسیدhydrochloric acid - اسید هیدروکلریک یا اسید کلریدریک یا جوهر نمک Peripheral arterial disease - بیماری شریانی محیطیobserved rate constant - ثابت نرخ مشاهده شدهDissociation constant - حد تفکیکDimethylsulfoxide - دیمتیل سولفواکسیدhuman coronary artery smooth muscle cells - سلول های عضلانی عروق کرونر انسانی انسانIn vitro pharmacology - فارماکولوژی in vitroFLuorescence Imaging Plate Reader - فلورسانس تصویربرداری صفحه خوانندهkon - می تواندmillimolar - میلی آمپرmilliliter - میلی لیترmicromolar - میکرومولارnanomolar - نانومولارPlatelet rich plasma - پلاسما غنی از پلاکتPlatelets - پلاکت هاMagnesium chloride - کلرید منیزیمPotassium chloride - کلرید پتاسیمCalcium chloride - کلسیم کلرید
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Vorapaxar is a novel protease-activated receptor-1 (PAR1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. The present study provides a comprehensive in vitro pharmacological characterization of vorapaxar interaction with the PAR1 receptor on human platelets. Similar studies were performed with a metabolite of vorapaxar (M20). Vorapaxar and M20 were competitive PAR1 antagonists that demonstrated concentration-dependent, saturable, specific, and slowly reversible binding to the receptor present on intact human platelets. The affinities of vorapaxar and M20 for the PAR1 receptor were in the low nanomolar range, as determined by saturation-, kinetic- and competitive binding studies. The calculated Kd and Ki values for vorapaxar increased in the presence of plasma, indicating a decrease in the free fraction available for binding to the PAR1 receptor on human platelets. Vorapaxar was also evaluated in functional assays using thrombin or a PAR1 agonist peptide (SFLLRN). Vorapaxar and M20 completely blocked thrombin-stimulated PAR1/β-arrestin association in recombinant cells and abolished thrombin-stimulated calcium influx in washed human platelets and vascular smooth muscle cells. Moreover, vorapaxar and M20 inhibited PAR1 agonist peptide-mediated platelet aggregation in human platelet rich plasma with a steep concentration response relationship. Vorapaxar exhibited high selectivity for inhibition of PAR1 over other platelet GPCRs. In conclusion, vorapaxar is a potent PAR1 antagonist exhibiting saturable, reversible, selective binding with slow off-rate kinetics and effectively inhibits thrombin's PAR1-mediated actions on human platelets.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 762, 5 September 2015, Pages 221-228
Journal: European Journal of Pharmacology - Volume 762, 5 September 2015, Pages 221-228
نویسندگان
Brian E. Hawes, Ying Zhai, David Hesk, Mark Wirth, Huijun Wei, Madhu Chintala, Dietmar Seiffert,