TABLE 2

Agonist response to compounds as determined from CRE-SPAP gene transcription in CHO-β1 and CHO-β2 cells given as log Embedded Image values and % 10 μM isoprenaline responses in n separate experiments

Agonist responses were also examined in the presence of CGP20712A (β1AR) or ICI118551 (β2AR), and where a parallel shift was achieved, a log Embedded Image value for the antagonist is also given. No response was seen for CGP20712A, ICI118551, nor the docking screen compounds 13a, 14a, 15a, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 (n = 5 for each ligand at each receptor).

Compoundβ1ARβ2ARLog(Efficacy Ratio)
Log Embedded Image% IsopnLog Embedded ImageCGP20712AnLog Embedded Image% IsopnLog Embedded ImageICI118551nβ1ARβ2AR
Literature known reference compounds
 Cimaterol−8.6 ± 0.1100 ± 912−9.0 ± 0.120−9.7 ± 0.198 ± 612−9.7 ± 0.1232.212.59
 Salbutamol−6.5 ± 0.2109 ± 97−9.0 ± 0.26−8.6 ± 0.195 ± 66−9.8 ± 0.171.552.39
 Salmeterol−6.8 ± 0.1110 ± 97−8.9 ± 0.34−10.9 ± 0.2100 ± 78−9.1 ± 0.061.021.81
 Denopamine−8.1 ± 0.1101 ± 47−9.2 ± 0.34−6.4 ± 0.165 ± 67−9.6 ± 0.142.131.02
 CGP 12177−8.5 ± 0.182 ± 713−7.0 ± 0.17−9.7 ± 0.137 ± 410−9.6 ± 0.114−0.920.16
Compounds chosen from docking calculations
 1−7.5 ± 0.180 ± 48−8.6 ± 0.17−8.0 ± 0.190 ± 67−9.6 ± 0.161.21.76
 2−7.2 ± 0.182 ± 67−8.6 ± 0.25−7.5 ± 0.197 ± 47−9.5 ± 0.161.221.64
 3−6.3 ± 0.133 ± 66−7.0 ± 0.195 ± 86−9.6 ± 0.151.271.39
 4−6.7 ± 0.160 ± 67−7.1 ± 0.179 ± 47−9.5 ± 0.161.251.24
 11a−6.6 ± 0.1113 ± 76−9.4 ± 0.33−6.5 ± 0.192 ± 96−9.7 ± 0.251.351.23
 5−7.0 ± 0.285 ± 76−9.1 ± 0.34−6.5 ± 0.186 ± 116−9.6 ± 0.151.421.19
 12a−7.3 ± 0.178 ± 67−9.3 ± 0.15−7.2 ± 0.196 ± 96−9.7 ± 0.161.101.05
 6−6.8 ± 0.182 ± 96−9.0 ± 0.23−6.6 ± 0.175 ± 86−9.8 ± 0.150.920.89
 7−6.9 ± 0.090 ± 56−9.1 ± 0.23−6.6 ± 0.186 ± 67−9.6 ± 0.161.090.73
 810 μM = 21 ± 78−6.2 ± 0.135 ± 76
 910 μM = 30 ± 12710 μM = 29 ± 47
 10No response610 μM = 50 ± 87
  • Isop, isoprenaline.

  • a Molecules selected from secondary screen.