Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist

In this study, 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, (BR-AEA), was designed, synthesized, characterized and tested in docking studies and in vitro. Previous to its synthesis, a set of compounds, including well-known ligands and boron containing compounds, were studied under docking simulations. BR-AEA showed greater affinity than these well-known agonists and was found to be slightly closer than salbutamol to the residues in the TM5 and TM3 of the beta(2) adrenoceptor (beta(2)AR), making a greater number of interactions with them, including some that are apparently key to greater affinity and beta(2)AR activation. This study suggests that affinity is closely related to the interactions of the boron atom, as well as the capacity of boronic acid moieties to make a network of hydrogen bonds with the beta(2)AR. In vitro, the relaxing effects of BR-AEA on isolated guinea pig tracheal rings were compared with salbutamol. The EC50 values for BR-AEA were at least five-fold lower than for salbutamol, showing the greater potency of the former. Additionally, propranolol and ICI 118,551 showed competitive antagonism in relation to the relaxing effect of the test compound (pA(2) 6.204 +/- 0.367 and 9.089 +/- 0.470, respectively). (C) 2009 Elsevier Masson SAS. All rights reserved.