The Affinity Of β-adrenoceptor Antagonists For The Polymorphic Variants Of The Human β1-adrenoceptor

Richard Proudman, Stephen Hill, Jillian Baker. University of Nottingham, Nottingham, UK

There are 2 naturally occurring polymorphic variants of the human β1-adrenoceptor – serine or glycine at position 49 in the N-terminus and glycine or arginine at position 389 in the C-terminus. Several clinical studies suggest that patient response to β-blockers depends upon the polymorphic alleles expressed. Better clinical outcomes are seen in studies using carvedilol, atenolol, metoprolol and bucindolol in patients homozygous for Arg389 than those with a gly389 allele. Arg 389 has therefore been suggested to have higher sensitivity to β-blockers (Azuma and Nonen 2009; Brodde 2008). This study examined the affinity of clinically used β-blockers for these polymorphic variants.

CHO-K1 cells were transfected with the human wildtype (WT) β1-adrenoceptor (ser49/gly389) or each polymorphic variant (gly49/gly389 or ser49/arg389), stable cell lines made by dilution cloning and antagonist affinity assessed by 3H-CGP 12177 whole cell binding (Baker 2005)

The affinity of 3H-CGP 12177 obtained from saturation binding was 0.36±0.04nM n = 11, 0.38 ± 0.03 n = 10 and 0.45 ± 0.04 n = 9 for the WT, gly49 and arg389 variants respectively. The affinities of β-antagonists from competition binding are given in the table.

Table showing the log KD values (mean + s.e.m.) for a range of β-blockers obtained from whole cell binding at the human β1-AR and β2-AR. n = number of separate experiments.

There was no difference in the affinity of β-blockers for the polymorphic variants of the human β1-adrenoceptor when examined in a transfected cell system. It is therefore unlikely that the different clinical responses seen are due to different β-antagonist affinities for the polymorphic variants.

Azuma and Nonen (2009) Eur J Clin Pharmacol 65: 3-17

Baker (2005) Brit J Pharmacol 144: 317-322

Brodde (2008) Fundam Clin Pharmacol. 22: 107-25.