Discovery of ß-arrestin-biased ß2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

ß-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ß-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ß-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 ß2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their ß-adrenoceptor-mediated 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 ß-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ß-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-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of ß-arrestin-biased ß2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

A Selective Pharmacophore Model for beta(2)-Adrenoceptor Agonists.

Beta(2)-adrenoceptor selectivity is an important consideration in drug design in order to minimize the possibility of side effects. A selective pharmacophore model was developed based on a series of selective beta(2)-adrenoceptor agonists. The best pharmacophore hypothesis consisted of five chemical features (one hydrogen-bond acceptor, one hydrogen-bond donor, two ring aromatic and one positive ionizable feature). The result was nearly in accordance with the reported interactions between the beta(2)-adrenoceptor and agonists, and it shared enough similar features with the result of field point patterns by FieldTemplater, which mainly validated the pharmacophore model. Moreover, the pharmacophore could predict the selectivity over the beta(1)-adrenoceptor. These results might provide guidance for the rational design of novel potent and selective beta(2)-adrenoceptor agonists.

Design, synthesis and antitumor activity of aromatic urea-quinazolines.

Background: Gefitinib and sorafenib have been proved effective for the treatment of cancers in clinical practice for years. Materials & methods: We intended to integrate the structural features of gefitinib and sorafenib and construct structurally unique 7-aromatic ureido-4-anilinoquinazolines. Results: Most of the targets exhibited promising antitumor activities. 8u showed excellent antitumor activities against the three tested cell lines (IC50, 0.81-2.49 µM). The enzymatic, apoptosis assay of 8u were also performed to study their preliminary action of mechanism. Conclusion: 8u deserve further research as antitumor agents.