TRV120027 是血管紧张素 II 受体 1 型 (AT1R) 的 β-arrestin-1 激动剂。TRV120027 通过阳离子通道亚家族 C3 (TRPC3) 偶联诱导急性儿茶酚胺分泌，促进质膜上 AT1R-β-arrestin-1-TRPC3-PLCγ 形成大分子复合物。TRV120027 抑制血管紧张素 II 介导的血管收缩并增加心肌细胞的收缩力。TRV120027 有潜力用于急性失代偿性心力衰竭 (ADHF) 的研究。
IC50: the angiotensin II receptor type 1 (AT1R)[1]
TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), engages ?-arrestins while blocking G-protein signaling[1]. TRV120027?induces?acute?catecholamine?secretion?through cation channel subfamily C3 (TRPC3) coupling, promotes the formation of a macromolecular complex composed of AT1R-β-arrestin-1-TRPC3-PLCγ at the plasma membrane. TRV120027 inhibits angiotensin II-mediated vasoconstriction and increases cardiomyocyte contractility. TRV120027 has the potential for the?acute decompensated heart failure (ADHF) treatment[2].
TRV120027 (100 nM) significantly increases the AT1R and TRPC3 association with the immunoprecipitated β-arrestin-1 in?HEK293 cells co-transfected with Flag-AT1R-cherry, HA-β-arrestin-1 and TRPC3-GFP[2].
TRV120027 (100 nM) induces an [Ca2+]i?increase in HEK293 cells co-transfected with AT1R, β-arrestin-1, and TRPC3, which are significantly blocked by Pyr3 pre-incubation?in HEK293 cells co-transfected with Flag-AT1R-Cherry, HA-β-arrestin-1, and TRPC3-GFP[2].
TRV120027 (intravenous?injection; 0.3 or 1.5 µg/kg per minute; infusion rate, 0.5 mL/min) when added to furosemide decreases cardiac preload and afterload, systemic and renal vascular resistances, and left ventricular external work while increasing cardiac output and renal blood flow. GFR and renal excretory function are maintained in canines with experimental HF[1].
| Animal Model: | Male mongrel dogs (weight, 20.5-30 kg)[1] |
| Dosage: | 0.3 or 1.5 µg/kg per minute; infusion rate, 0.5 mL/min |
| Administration: | Intravenous?injection |
| Result: | Resulted in dose-dependent vasodilation, increased cardiac contractility, and decreased myocardial oxygen consumption in dog. |
[1]. Boerrigter G, et al. TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure.Circ Heart Fail. 2012 Sep 1;5(5):627-34. Epub 2012 Aug 13.
[2]. Liu CH, et al. Arrestin-biasedAT1RagonisminducesacutecatecholaminesecretionthroughTRPC3coupling.Nat Commun.2017 Feb 9;8:14335.
动态评分
0.0