Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling

Abstract

Sir James Black developed β-blockers, one of the most useful groups of drugs in use today. Not only are they being used for their original purpose to treat angina and cardiac arrhythmias, but they are also effective therapeutics for hypertension, cardiac failure, glaucoma, migraine and anxiety. Recent studies suggest that they might also prove useful in diseases as diverse as osteoporosis, cancer and malaria. They have also provided some of the most useful tools for pharmacological research that have underpinned the development of concepts such as receptor subtype selectivity, agonism and inverse agonism, and ligand-directed signalling bias. This article examines how β-blockers have evolved and indicates how they might be used in the future.

Figure 1

Biased signalling from the β₂-adrenoceptor in response to propranolol in CHO-K1 cells . The presence of different intracellular signalling proteins (e.g. Gαs or β-arrestin) bound to the β₂-adrenoceptor provides an allosteric mechanism for reciprocal interaction between the signalling protein and the orthosteric ligand binding site. However, the extent to which a particular signalling pathway predominates will depend on both the affinity of ligands for particular receptor–effector complexes and the degree of compartmentalisation of these complexes within the cell.