The selectivity of β-adrenoceptor agonists at the human β1 and β2-adrenoceptors

Jillian Baker. University of Nottingham, Nottingham, United Kingdom.

There are two important properties of agonist-receptor interactions; affinity (ability to bind to the receptor) and efficacy (ability of the agonist-receptor complex to induce a response; Strange 2008). Theoretically, agonists could be selective because of selective affinity, selective intrinsic efficacy or both. This study examined affinity and intrinsic efficacy of β-adrenoceptor agonists at the human β1 and 2-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy.

Stable clonal CHO-K1 cell lines, transfected with either the human β1 or β2-adrenoceptor, were used and whole cell 3H-CGP 12177 radioligand binding and 3H-cAMP accumulation measured as previously described (Baker and Hill 2007).

Several agonists were found to be highly subtype selective because of β2-selective affinity e.g. salmeterol (log KD β2 -9.26±0.06, n = 10: β1 -5.73±0.03,n = 11) and formoterol (log KD β2 -8.63±0.02, n = 8; β1 -6.11±0.05,n = 8) whilst others had little affinity-selectivity e.g. isoprenaline (log KD β2-6.64±0.09,n = 11 β1 -6.06±0.08,n = 9). However the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar at both receptor subtypes. Other ligands (e.g. denopamine for β1, clenbuterol, salbutamol for β2) were found to have subtype selective intrinsic efficacy. Thus, there are agonists with subtype selectivity based upon either selective affinity or selective intrinsic efficacy. There is therefore scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy.

A) Plot of log KD for agonists for β1 vs β2-adrenoceptors. Salmeterol is highly β2-selective based on affinity. Isoprenaline, denopamine and AZ 40140 have little selectivity based on affinity.

B) Plot of intrinsic efficacy ratios (log KD/log EC50) for the same compounds. The line of best fit the slope is not 1 not does it go though the origin as this represents a function of efficacy (i.e. cell line differences e.g. receptor number, receptor-effector coupling etc.) Denopamine is β1-selective, AZ 40140d is β2-selective and isoprenaline and salmeterol non-selective based on efficacy.

References

Baker JG and Hill SJ (2007) J Pharmacol Exp Ther 320: 218-228.

Strange PG (2008) Brit J Pharmacol 153: 1353-1363.

JGB is a Wellcome Trust Clinician Scientist Fellow