Insights into a defined secondary binding region on β-adrenoceptors and putative roles in ligand binding and drug design

Increasing evidence points to the possibility of one or more secondary binding sites being involved in the interaction of catecholamines on their receptors. However, the importance of these sites has not yet been clearly established. In this review, we examine the possibility that catecholamines reach a defined secondary binding region on beta adrenoceptors attempting to analyze the approach of these ligands to this binding site. Inferences are made as to the possible effects on receptor activity when a compound interacts with the orthosteric binding site, the secondary binding region, or both in a concerted manner. Consideration is given to prolonged ligand interaction with orthosteric and allosteric binding sites, biased signaling, and feasible cellular responses, as well as to the importance of these effects in physiological processes when these receptors are targets for drug design.