β2AR agonist | BI-167107
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Highlights
β2 adrenergic receptor (β2AR ) agonists have been used as bronchodilating agents for the last decades for the treatment of pulmonary diseases like asthma. BI-167107 was synthesized during a campaign to develop third generation of β2-agonists. Due to its high potency and slow dissociation from the target BI-167107 was subsequently used to support crystallization of active state β2AR and β2AR-G-protein complexes. Interestingly BI-167107 is also very active agonist of the β1AR (IC50 = 3.2 nM) and shows some activity as α1A antagonist (IC50 = 32 nM). Therefore the compound could be employed for the crystallization of other receptors.1-5 BI-167107 should be used only as a tool to support crystallization studies and will be shipped free of charge in 2 mg batches to researchers.
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Target information
G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet only recently we started to understand the molecular processes through which they bind to their endogenous agonists and activate effector proteins. β2AR is a member of the class A family of GPCRs. Besides rhodopsin it is the best characterized member of that family.
Human beta2 adrenoreceptor in the active state, in complex with BI-167107 (PDB code: 3p0g).
In vitro Activity
We recommend using this compound only to support the crystallization of beta receptors.
BI-167107 is a potent and long acting beta agonist with a KD of 84 pM.
|
Probe name |
BI-167107 |
|
MW [Da] |
370.4 |
|
KD1 [nM] |
0.084 |
|
Bmax1 |
2238 |
|
EC50 cAMP accumulation1 [nM] |
0.05 |
|
t1/2 (dissociation half-life)1 [h] |
30 |
For further information on assays please refer to reference 1.
Selectivity
BI-167107 is not a selective beta2 agonist.
A Cerep screen revealed several hits >70% inhibition at 10µM and IC50s were consequently measured for eight targets. Two showed strong activity in the low nanomolar range: β1(h) (agonist radioligand) (IC50 = 3.2 nM), α1A(h) (antagonist radioligand) (IC50 = 32 nM). BI-167107 showed weaker activity on the other targets: 5-HT transporter (h) (antagonist radioligand) (IC50 = 6.1 µM ), 5-HT1A(h) (agonist radioligand) (IC50 = 1.4 µM), 5-HT1B (antagonist radioligand) (IC50 = 0.25 µM), D2S(h) (agonist radioligand) (IC50 = 5.9 µM), dopamine transporter(h) (antagonist radioligand) (IC50 = 7.2 µM), μ (MOP) (h) (agonist radioligand) (IC50 = 6.5 µM).
The data is available for download.
Co-crystal structure of the BI probe compound and the target protein
|
PDB ID |
Title |
|
3P0G |
Structure of a nanobody-stabilized active state of the beta2 adrenoceptor |
|
4LDE |
Structure of beta2 adrenoceptor bound to BI-167107 and an engineered nanobody |
|
3SN6 |
Crystal structure of the beta2 adrenergic receptor-Gs protein complex |
Summary
β2 adrenergic receptor (β2AR ) agonists have been used as bronchodilating agents for the last decades for the treatment of pulmonary diseases like asthma. BI-167107 was synthesized during a campaign to develop third generation of β2-agonists suitable for a once a day regimen. Due to its high potency and slow dissociation from the target it was subsequently used to support crystallization of active state β2AR and β2AR-G-protein complexes. The compound could potentially be employed for the crystallization of other beta receptors.1-5
Efforts to obtain an agonist-bound active-state GPCR structures have proven difficult due to the inherent instability of this state in the absence of a G protein. Here, BI-167107 has proven itself to be a valuable tool: the compound is an ultra-high affinity agonist with a dissociation half-life of more than 30 h ensuring that the β2AR would be occupied by an agonist at all times.1 BI-167107 was subsequently used in various studies in β2AR structure and dynamics. BI-167107 may also prove useful as a tool for the study of other isoforms.
BI-167107 should be used only as a tool to support crystallization studies.
Supplementary data
2 D structure formats available
References
Structure of a nanobody-stabilized active state of the β2 adrenoceptor
Rasmussen S. G. F., Choi H.-J., Fung J. J., Pardon E., Casarosa P., Chae P. S., DeVree B. T., Rosenbaum D. B., Thian F. S, Kobilka T. S., Schnapp A, Konetzki I., Sunahara R. K., Gellman S. H., Pautsch A., Steyaert J., Weis W. I., Kobilka B. K.
Nature 2011, 469, 175-180
Crystal structure of the β2 adrenergic receptor-Gs protein complex
Rasmussen S. G. F., DeVree B. T., Zou Y., Kruse A. C., Chung K. Y., Kobilka T. S., Thian F. S., Chae P. S., Pardon E., Calinski D., Mathiesen J. M., Shah S. T. A., Lyons J. A., Caffrey M., Gellman S. H., Steyaert J., Skiniotis G., Weis W. I., Sunahara R. K., Kobilka B. K.
Nature 2011, 477, 549-555
Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody
Ring A. M., Manglik A., Kruse A. C., Enos M. D., Weis W. I., Garcia K. C., Kobilka B. K.
Nature 2013, 502, 575-579
The Structural Basis of G-Protein-Coupled Receptor Signaling (Nobel Lecture)
Kobilka B.
Angew. Chem. Int. Ed. 2013, 52, 6380-6388
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling
Manglik A., Kim T. H., Masureel M., Altenbach C., Yang Z., Hilger D., Lerch M. T., Kobilka T. S., Thian F. S., Hubbell W. L., Prosser R. S., Kobilka B. K.
Cell 2015, 161, 1101-1111
