The selectivity of β‐adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors

Abstract

β‐Adrenoceptor antagonists (‘β‐blockers’) are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at β1‐adrenoceptors), while the worrisome side effects of bronchospasm result from airway β2‐adrenoceptor blockade. The aim of this study was to determine the selectivity of β‐antagonists for the human β‐adrenoceptor subtypes. 3H‐CGP 12177 whole cell‐binding studies were undertaken in CHO cell lines stably expressing either the human β1‐, β2‐ or the β3‐adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background. In this study, the selectivity of well‐known subtype‐selective ligands was clearly demonstrated: thus, the selective β1 antagonist CGP 20712A was 501‐fold selective over β2 and 4169‐fold selective over β3; the β2‐selective antagonist ICI 118551 was 550‐ and 661‐fold selective over β1 and β3, respectively, and the selective β3 compound CL 316243 was 10‐fold selective over β2 and more than 129‐fold selective over β1. Those β2‐adrenoceptor agonists used clinically for the treatment of asthma and COPD were β2 selective: 29‐, 61‐ and 2818‐fold for salbutamol, terbutaline and salmeterol over β1, respectively. There was little difference in the affinity of these ligands between β1 and β3 adrenoceptors. The clinically used β‐antagonists studied ranged from bisoprolol (14‐fold β1‐selective) to timolol (26‐fold β2‐selective). However, the majority showed little selectivity for the β1‐ over the β2‐adrenoceptor, with many actually being more β2‐selective. This study shows that the β1/β2 selectivity of most clinically used β‐blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘β1‐selective’ actually have higher affinity for the β2‐adrenoceptor. There is therefore considerable potential for developing more selective β‐antagonists for clinical use and thereby reducing the side‐effect profile of β‐blockers. British Journal of Pharmacology (2005) 144, 317–322. doi:10.1038/sj.bjp.0706048