TABLE 3

The ratio of the log KB value for CGP12177 (as an antagonist of cimaterol; thus, at the high-affinity conformation) and log EC50 value for CGP12177 (as an agonist of the secondary low-affinity conformation) for responses seen at the β1-WT and β1-TM chimeric receptors (data taken from Table 2)

The ratios of the affinity for antagonists at the two conformations (i.e., log KB for antagonism of cimaterol at high-affinity site/log KB for antagonism of CGP12177 at low-affinity site) were determined. This table examines the ratio of the affinities of ligands at the two conformations of the β1-adrenoceptor and thus allows for differences in absolute affinity. For example, ICI118551 has a higher affinity at the β1-TM7 receptor (Table 2) than the β1-WT receptor; however, the ratio of the affinity in the presence of cimaterol and CGP 12177 is similar to that at the WT receptor, suggesting that although the β1-TM7 mutation alters the affinity of ICI118551, it does not alter the secondary conformation. The most consistent change is seen with the β1-TM4 mutation, where the ratios are all nearly 0, suggesting no difference in affinity (i.e., no secondary conformation).

Ratio of Log KB CGP12177/ Log EC50 CGP12177Ratio of Log KB (Cimaterol as Agonist)/Log KB (CGP12177 as Agonist)
CGP20712ABisoprololICI118551PropranololCarvedilol
β1-WT1.372.022.651.062.342.64
β1-TM11.941.942.881.172.112.16
β1-TM21.631.651.431.601.651.01
β1-TM31.421.892.601.482.222.47
β1-TM40.360.01−0.020.140.140.08
β1-TM51.772.412.601.302.472.43
β1-TM61.752.552.882.152.852.89
β1-TM72.311.592.521.132.532.71