Cell-based assays and molecular dynamics analysis of a boron-containing agonist with different profiles of binding to human and guinea pig beta2 adrenoceptors.

The design of beta2 adrenoceptor (β2 AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with β2 AR are interesting because it is considered a prototype for G-protein coupled receptors. Preclinical studies for agonist development have involved biological assays with guinea pigs due to a similar physiology to humans. Boron-containing Albuterol derivatives (BCADs) designed as bronchodilators have improved potency and efficacy compared with their boron-free precursor on guinea pig β2 ARs (gpβ2 ARs), and two of the BCADs (BR-AEA and boronterol) conserve these features on cells expressing human β2 ARs (hβ2 ARs). The aim of this study was to test the BCAD Politerol on gpβ2 ARs and hβ2 ARs in vitro and in silico. Politerol displayed higher potency and efficacy on gpβ2 AR than on hβ2 AR in experimental assays, possible explanations are provided based on molecular modeling, and molecular dynamics simulations of about 0.25 µs were performed for the free and bound states adding up to 2 µs in total. There were slight differences, particularly in the role of the boron atom, in the interactions of Politerol with gpβ2 ARs and hβ2 ARs, affecting movements of transmembrane domains 5-7, known to be pivotal in receptor activation. These findings could be instrumental in the design of compounds selective for hβ2 ARs.