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 (β ₂ AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with β ₂ 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 β ₂ ARs (gpβ ₂ ARs), and two of the BCADs (BR-AEA and boronterol) conserve these features on cells expressing human β ₂ ARs (hβ ₂ ARs). The aim of this study was to test the BCAD Politerol on gpβ ₂ ARs and hβ ₂ ARs in vitro and in silico. Politerol displayed higher potency and efficacy on gpβ ₂ AR than on hβ ₂ 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 gpβ ₂ ARs and hβ ₂ 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 hβ ₂ ARs.