BI-167107
目录号 : GC38378
BI-167107 是一种高亲和力的 β2 肾上腺素能受体 (β2AR) 完全激动剂，与 β2 肾上腺素能受体 (β2AR) 结合，解离常数 Kd 为 84 pM。
Cas No.:1202235-68-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BI-167107 is a high affinity, full agonist that binds to the β2 adrenergic receptor (β2AR) with a dissociation constant Kd of 84 pM[1].
Compared to other βAR ligands, BI-167107 displays nanomolar affinities and slow off-rates[1].
[1]. Rasmussen SG, et al. Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature. 2011 Jan 13;469(7329):175-80.
| Cas No. | 1202235-68-4 | SDF | |
| Canonical SMILES | O=C1NC(C(O)=CC=C2C(O)CNC(C)(CC3=C(C=CC=C3)C)C)=C2OC1 | ||
| 分子式 | C21H26N2O4 | 分子量 | 370.44 |
| 溶解度 | DMSO: 75 mg/mL (202.46 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6995 mL | 13.4975 mL | 26.9949 mL |
| 5 mM | 0.5399 mL | 2.6995 mL | 5.399 mL |
| 10 mM | 0.2699 mL | 1.3497 mL | 2.6995 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
High-Affinity Functional Fluorescent Ligands for Human β-Adrenoceptors
Sci Rep 2017 Sep 26;7(1):12319.PMID:28951558DOI:10.1038/s41598-017-12468-3.
Visualization of the G-protein coupled receptor (GPCR) is of great importance for studying its function in a native cell. We have synthesized a series of red-emitting fluorescent probes targeting β-adrenergic receptor (βAR) that are compatible with confocal and Stimulated Emission Depletion (STED) microscopy as well as with Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay in living cells. The probe based on the agonist BI-167107 and fluorescent dye KK114 demonstrates nanomolar binding affinity and up to nine-fold β2AR selectivity over β1AR. Carazolol-derived probes are fluorogenic and allow no-wash imaging experiments. STED microscopy of β2ARs stained at the native expression level on pancreatic CAPAN cells provides two-fold improvement in lateral optical resolution over confocal mode and reveals the formation of receptor microdomains. These probes retain their functional (agonist or antagonist) properties, allowing simultaneous modulation of cyclic adenosine monophosphate (cAMP) levels and receptor internalization as well as imaging receptor localization.
Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR
Cell Res 2021 May;31(5):569-579.PMID:33093660DOI:10.1038/s41422-020-00424-2.
Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β1AR and β2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β1AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β1AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β1AR and β2AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.
Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists
J Med Chem 2017 Jun 8;60(11):4693-4713.PMID:28489379DOI:10.1021/acs.jmedchem.7b00363.
By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β2-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D2R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by the presence of an endocyclic H-bond donor.
Analysis of β2AR-Gs and β2AR-Gi complex formation by NMR spectroscopy
Proc Natl Acad Sci U S A 2020 Sep 15;117(37):23096-23105.PMID:32868434DOI:10.1073/pnas.2009786117.
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein Gs and stimulates cAMP formation. Functional studies have shown that the β2AR also couples to inhibitory G protein Gi, activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001, re15 (2001)]. A crystal structure of the β2AR-Gs complex revealed the interaction interface of β2AR-Gs and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549-555 (2011)], yet, the dynamic process of the β2AR signaling through Gs and its preferential coupling to Gs over Gi is still not fully understood. Here, we utilize solution nuclear magnetic resonance (NMR) spectroscopy and supporting molecular dynamics (MD) simulations to monitor the conformational changes in the G protein coupling interface of the β2AR in response to the full agonist BI-167107 and Gs and Gi1 These results show that BI-167107 stabilizes conformational changes in four transmembrane segments (TM4, TM5, TM6, and TM7) prior to coupling to a G protein, and that the agonist-bound receptor conformation is different from the G protein coupled state. While most of the conformational changes observed in the β2AR are qualitatively the same for Gs and Gi1, we detected distinct differences between the β2AR-Gs and the β2AR-Gi1 complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of Gs These differences between the β2AR-Gs and β2AR-Gi1 complexes in ICL2 may be key determinants for G protein coupling selectivity.
Computational study on the different ligands induced conformation change of β2 adrenergic receptor-Gs protein complex
PLoS One 2013 Jul 29;8(7):e68138.PMID:23922653DOI:10.1371/journal.pone.0068138.
β2 adrenergic receptor (β2AR) regulated many key physiological processes by activation of a heterotrimeric GTP binding protein (Gs protein). This process could be modulated by different types of ligands. But the details about this modulation process were still not depicted. Here, we performed molecular dynamics (MD) simulations on the structures of β2AR-Gs protein in complex with different types of ligands. The simulation results demonstrated that the agonist BI-167107 could form hydrogen bonds with Ser203(5.42), Ser207(5.46) and Asn293(6.55) more than the inverse agonist ICI 118,551. The different binding modes of ligands further affected the conformation of β2AR. The energy landscape profiled the energy contour map of the stable and dissociated conformation of Gαs and Gβγ when different types of ligands bound to β2AR. It also showed the minimum energy pathway about the conformational change of Gαs and Gβγ along the reaction coordinates. By using interactive essential dynamics analysis, we found that Gαs and Gβγ domain of Gs protein had the tendency to separate when the inverse agonist ICI 118,551 bound to β2AR. The α5-helix had a relatively quick movement with respect to transmembrane segments of β2AR when the inverse agonist ICI 118,551 bound to β2AR. Besides, the analysis of the centroid distance of Gαs and Gβγ showed that the Gαs was separated from Gβγ during the MD simulations. Our results not only could provide details about the different types of ligands that induced conformational change of β2AR and Gs protein, but also supplied more information for different efficacies of drug design of β2AR.