Pharmacological characterization of CGP 12177 at the human β 2 ‐adrenoceptor

It has recently been reported that CGP 12177 can act as an agonist at a novel secondary site within the human β 1 ‐adrenoceptor. The aim of this study was to undertake a detailed pharmacological study of the effects of CGP 12177 on the human β 2 ‐adrenoceptor. CGP 12177 acted as a potent partial agonist of 3 H‐cyclic AMP accumulation (log EC 50 −8.90±0.06) and CRE‐mediated reporter gene transcription (log EC 50 −9.66±0.04) in CHO‐K1 cells expressing the human β 2 ‐adrenoceptor. These CGP‐induced responses were antagonized by the β 2 ‐selective antagonist ICI 118551 (apparent log K D values of −8.84±0.15 and −9.51±0.02 for the cyclic AMP and reporter gene responses respectively). CGP 12177 was also able to antagonize both cyclic AMP and reporter gene responses to more efficacious β 2 ‐agonists with similar log K D values (e.g. −9.57±0.15 and −10.04±0.096 respectively with salbutamol as agonist).3 H‐CGP 12177 binding to β 2 ‐adrenoceptors in intact CHO‐β 2 cells yielded a log K D value of −9.84±0.06, but indicated that the ligand dissociates very slowly from the receptor (t ½ for dissociation=65 min). However, studies with a Green Fluorescent Protein (GFP)‐tagged β 2 ‐adrenoceptor indicated that CGP 12177 does not stimulate β 2 ‐adrenoceptor internalization. This study demonstrates that CGP 12177 is a high affinity partial agonist of both cAMP accumulation and CRE‐mediated gene transcription at the human β 2 ‐adrenoceptor. It provides no evidence that CGP 12177 can discriminate a secondary site on the β 2 ‐adrenoceptor analogous to that observed for the human β 1 ‐adrenoceptor. However, despite its very weak actions on cAMP accumulation, the potent agonist effects of CGP 12177 on CRE‐mediated gene transcription at the human β 2 ‐adrenoceptor, coupled with its long duration of action, offers a potential lead for drug development for the treatment of chronic inflammatory airway diseases.British Journal of Pharmacology (2002) 137 , 400–408. doi: 10.1038/sj.bjp.0704855