Biased Agonism at β-Adrenoceptor Subtypes: A Drug Development Perspective.

Selectivity of a drug for a desired response as compared to undesirable responses (side effect) is a key goal of drug development. Early concepts to achieve such selectivity were based on selectivity for a molecular target as compared to others, pharmacokinetic factors to achieve high concentrations in the target tissue as compared to low concentrations in others, differential efficacy in the target vs. others tissues, and leveraging the concept of cell type and tissue differences in expression levels of receptors and their related signaling molecules, which can be further complicated by alterations of such ratios in disease. Biased agonism occurs when one response is activated preferentially over another after accounting for the above other factors. Thus, assessment of ligand bias is not always easy. β-Adrenoceptors have played a relevant role in our understanding of the phenomenon of biased agonism. Several clinically used β-adrenoceptor ligands were proposed to exhibit biased agonism, but the findings often are inconclusive, at least partly based on the overall complexity of assessment of biased signaling. These complexities also make it challenging to determine the desired biased profile of a ligand at the start of a drug research and development project, particularly for innovative applications. Thus, biased agonism has potential to contribute to functional target selectivity, but its prospective use remains challenging.