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

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 β 1‐adrenoceptors), while the worrisome side effects of bronchospasm result from airway β 2‐adrenoceptor blockade. The aim of this study was to determine the selectivity of β ‐antagonists for the human β ‐adrenoceptor subtypes. 3 H‐CGP 12177 whole cell‐binding studies were undertaken in CHO cell lines stably expressing either the human β 1‐, β 2‐ or the β 3‐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 β 1 antagonist CGP 20712A was 501‐fold selective over β 2 and 4169‐fold selective over β 3; the β 2‐selective antagonist ICI 118551 was 550‐ and 661‐fold selective over β 1 and β 3, respectively, and the selective β 3 compound CL 316243 was 10‐fold selective over β 2 and more than 129‐fold selective over β 1. Those β 2‐adrenoceptor agonists used clinically for the treatment of asthma and COPD were β 2 selective: 29‐, 61‐ and 2818‐fold for salbutamol, terbutaline and salmeterol over β 1, respectively. There was little difference in the affinity of these ligands between β 1 and β 3 adrenoceptors. The clinically used β ‐antagonists studied ranged from bisoprolol (14‐fold β 1‐selective) to timolol (26‐fold β 2‐selective). However, the majority showed little selectivity for the β 1‐ over the β 2‐adrenoceptor, with many actually being more β 2‐selective. This study shows that the β 1/ β 2 selectivity of most clinically used β ‐blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘ β 1‐selective’ actually have higher affinity for the β 2‐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