About BI-167107- a high-affinity β2AR full agonist

BI-167107 is a synthetic high-affinity agonist of the β2-adrenergic receptor (β2AR)[1]. It has a high potency and slow dissociation rate on β2AR and is used extensively in research, including the crystallization of β2-adrenergic receptor structures [2–5]. Besides β2AR, BI-167107 also shows affinity towards β1AR and α1AR.

Figure 1. 2D structures of BI-167107 and Isoproteneol downloaded from Pubchem

Experimental findings reveal that BI-167107 is a β-arrestin biased agonist of β2AR with a bias factor of 1.5 [6]. Biased agonism is a phenomenon in which an agonist ligand selectively activates one signaling pathway over the other. BI-167107 promotes β-arrestin mediated signaling 30 times more efficaciously than G protein-mediated signaling [6]. Unlike the balanced agonist isoproterenol (also an ethanolamine) that has one secondary amine, BI-167107 contains two secondary amines in its structure (Figure 1). This is proposed to be a possible explanation for its β arrestin-bias [7].

References

*1. Hoenke, C.; Bouyssou, T.; Tautermann, C. S.; Rudolf, K.; Schnapp, A.; Konetzki, I., Use of 5-hydroxy-4H-benzo [1, 4] oxazin-3-ones as β2-adrenoceptor agonists. Bioorganic & medicinal chemistry letters 2009, 19 (23), 6640–6644.*

*2. Rasmussen, S. G.; Choi, H.-J.; Fung, J. J.; Pardon, E.; Casarosa, P.; Chae, P. S.; DeVree, B. T.; Rosenbaum, D. M.; Thian, F. S.; Kobilka, T. S., Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 2011, 469 (7329), 175–180.*

*3. Rasmussen, S. G.; DeVree, B. T.; Zou, Y.; Kruse, A. C.; Chung, K. Y.; Kobilka, T. S.; Thian, F. S.; Chae, P. S.; Pardon, E.; Calinski, D., Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 2011, 477 (7366), 549–555.*

*4. Xu, X.; Kaindl, J.; Clark, M. J.; Hübner, H.; Hirata, K.; Sunahara, R. K.; Gmeiner, P.; Kobilka, B. K.; Liu, X., Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR. Cell Research 2021, 31 (5), 569–579.*

*5. Nguyen, A. H.; Thomsen, A. R.; Cahill, T. J.; Huang, R.; Huang, L.-Y.; Marcink, T.; Clarke, O. B.; Heissel, S.; Masoudi, A.; Ben-Hail, D., Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex. Nature structural & molecular biology 2019, 26 (12), 1123–1131.*

*6. Weiss, D. R.; Ahn, S.; Sassano, M. F.; Kleist, A.; Zhu, X.; Strachan, R.; Roth, B. L.; Lefkowitz, R. J.; Shoichet, B. K., Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor. ACS chemical biology 2013, 8 (5), 1018–1026.*

*7. Sanchez, J. E.; Kc, G. B.; Franco, J.; Allen, W. J.; Garcia, J. D.; Sirimulla, S., BiasNet: A Model to Predict Ligand Bias Toward GPCR Signaling. Journal of Chemical Information and Modeling 2021, 61 (9), 4190–4199.*