Discovery of β-arrestin-biased β2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives

Abstract

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.

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

“…Modifications of the 3- and 5-positions of the phenyl head group of the trantinterol scaffold have also produced a novel compound, 2f (2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile) that stimulates cAMP production through the β 2 adrenoreceptor with an EC50 of 0.25 nM and exhibits β2 receptor selectivity. 93 This compound induced smooth muscle relaxation in the isolated guinea pig trachea model that was attenuated by ICI-118551, an antagonist of β 2 -adrenergic receptor binding. The (S)-isomer was more active than the (R)-isomer.…”

“…Woo and colleagues 93 synthesized β-arrestin compounds with a 5-(1-amino-2- hydroxyethyl)-8-hydroxyquinolin-2(1H)-1 core structure that stimulates cellular cAMP production in vitro and induces bronchodilation in a guinea pig trachea relaxation assay, with bronchodilatory effects less robust than isoproterenol. These β-arrestin biased β 2 adrenoceptor agonists have a potential role as new therapeutics in the management of COPD.…”

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

“…Although “biased agonism” is often used in a sense to refer to “β-arrestin-biased agonism” in GPCR signaling ( 59 , 60 ), it generally describes the disparity of the efficacies of agonists in activating signals mediated by different downstream effectors, for example, different G protein isoforms, G protein versus β-arrestin, or biases from many other signaling pathways ( 61 ). In some cases, the biased agonist could act as an antagonist or an inverse agonist for G protein-dependent signaling but as an agonist for β-arrestin-dependent signaling in a single GPCR ( 62 , 63 ). Unlike G protein-mediated signaling pathways, which are transient and rapid, the β-arrestin-mediated pathway is often persistent and slow ( 58 , 64 , 65 ).…”

Recent Advances in β2-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure

“…Carvedilol was able to promote phosphorylation of the GRK sites on β 2 AR, recruitment of β-arrestins, β 2 AR internalization, and activation of extracellular signal-regulated kinase (ERK) while possessing an inverse efficacy in stimulating cAMP synthesis . Apart from these “extreme” examples of functional selectivity, a bias toward preferential β-arrestin over G s signaling or vice versa is another possibility . On the basis of the idea that β 2 AR desensitization contributes to the loss of bronchoprotective effect, it is expected that a β 2 -agonist with a signaling bias for G s over β-arrestin, such as salmeterol ( 2 ), , would be preferred over one with a reversed bias due to a lower potential to induce receptor desensitization.…”