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β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein-versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of β 2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their β-adrenoceptormediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter β-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and β-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of β-arrestin-biased β 2-adrenoceptor agonists, whereas salmeterol was found to be G s-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

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Ulcerative colitis (UC) is a common inflammatory bowel disease driven by the dyshomeostasis of intestinal immune system and microbiota, but its treatment options are limited due to impaired epithelial barrier integrity and function. Herein, a multifunctional biomimetic hydrogel is developed as artificial colonic mucosa, which can readily establish a bioadhesive barrier at the ulcer site and restore local immune and microbial homeostasis to exert potent anti-inflammatory effect. The hydrogel framework is generated through the thrombin-mediated activation and polymerization of fibrinogen that resembles natural blood coagulation mechanism. During this process, the antibacterial agent Ag + is used for the crosslinking between the generated fibrin units and dopamine/thiol-modified hyaluronic acid biopolymers via Ag + -thiol coordination to convey enhanced bioadhesiveness, while the interconnected porous network is employed to encapsulate basic fibroblast growth factor (bFGF) and alanyl-glutamine (ALG) for mucosa regeneration. The hydrogel stably adheres to the ulcer site to protect and repair the damaged epithelium and establishes an anti-inflammatory microenvironment by inducing locoregional M1-to-M2 macrophage repolarization while eliminating harmful gut flora, which can act in a cooperative manner to substantially alleviate UC symptoms. The biomimetic hydrogel here presents a promising approach for effective UC therapy in the clinics.