Background and purpose:  There are two important properties of receptor–ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor–ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 β‐adrenoceptor agonists at the three human β‐adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy.

Experimental approach:  Stable clonal CHO‐K1 cell lines, transfected with either the human β₁, β₂ or β₃‐adrenoceptor, were used, and whole‐cell [³H]‐CGP 12177 radioligand binding and [³H]‐cAMP accumulation were measured.

Key results:  Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the β₂‐adrenoceptor over the β₁ or β₃), while others (e.g. isoprenaline) had little affinity–selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for β₁; clenbuterol, AZ 40140d, salbutamol for β₂) were found to have subtype‐selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the β₁‐ and β₃‐adrenoceptors.

Conclusions and implications:  There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy.

This article is commented on by Kenakin, pp. 1045–1047 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00764.x