MK-0974
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
MK-0974(Telcagepant)是一种高效的、选择性的和可口服的CGRP受体拮抗剂,其IC50值为0.77 nM[1]。
降钙素基因相关肽(CGRP)受体是一种异二聚体的跨膜受体,由被称为降钙素受体样受体(CALCRL)的G蛋白偶联受体以及受体活性修饰蛋白1(RAMP1)组成。CGRP受体广泛地介导人体外周以及中枢神经系统中的CGRP活性。CGRP/CGRP受体信号通路调节呼吸、免疫和心血管系统的各种生理功能,并在偏头痛的病理生理过程中发挥关键作用。
配体受体结合实验表明,MK-0974对CGRP受体具有高亲和力,但对相关的人肾上腺髓质素受体没有亲和力,提示MK-0974的高度特异性[1]。在表达CGRP受体的HEK293细胞中,给予MK-0974阻止α-CGRP诱导的cAMP产生,显著抑制了CGRP受体活性。然而,加入50%的人血清降低了5倍的MK-0974抑制效力[1]。MK-0974可逆地和呈饱和性地结合到SK-N-MC细胞膜和恒河猴小脑,其Kd值分别为1.9 nM和1.3 nM[2]。
在恒河猴模型中,Capsaicin诱导的内源性CGRP释放导致真皮血管扩张。给予MK-0974可以呈剂量依赖性地抑制皮肤血管扩张,其中,阻止50%和90%的血流量增加分别需要127 nM和994 nM的血药浓度。对CGRP功能的抑制表明,MK-0974可以抑制CGRP受体[1]。在猴子模型中,MK-0974表现出适度的药物清除率(14 ~ 20 ml min-1 kg-1),而口服生物利用度为6%。在猴子中,MK-0974的药代动力学数据在0.5 ~ 10 mg kg-1的静脉注射剂量范围内呈线性,但血药浓度-时间曲线(AUC)下面积的增加(5 ~ 30 mg kg-1)是相应比例剂量的15倍以上[3]。
参考文献:
[1] Salvatore C A et al., Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther. 2008, 324(2): 416-421.
[2] Moore E L et al., Examining the binding properties of MK-0974: a CGRP receptor antagonist for the acute treatment of migraine. Eur J Pharmacol. 2009, 602(2-3): 250-254.
[3]. Roller S et al., Preclinical pharmacokinetics of MK-0974, an orally active calcitonin-gene related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences. Xenobiotica. 2009, 39(1): 33-45.
Storage | Store at -20°C |
M.Wt | 566.54 |
Cas No. | 781649-09-0 |
Formula | C26H27F5N6O3 |
Synonyms | Telcagepant;MK0974;MK 0974 |
Solubility | Soluble in DMSO |
Chemical Name | N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide |
SDF | Download SDF |
Canonical SMILES | C1CC(C(=O)N(CC1C2=C(C(=CC=C2)F)F)CC(F)(F)F)NC(=O)N3CCC(CC3)N4C5=C(NC4=O)N=CC=C5 |
运输条件 | 蓝冰运输或根据您的需求运输。 |
一般建议 | 不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。溶液形式一般不宜长期储存,请尽快用完。 |
描述 | MK-0974(Telcagepant)是一种高效的、选择性的和可口服的CGRP受体拮抗剂,对人类和恒河猴CGRP受体的Ki值分别为0.77 nM和1.2 nM。 | |||||
靶点 | CGRP receptor | |||||
IC50 | 0.77 nM and 1.2 nM (Human and rhesus CGRP,Ki) |