title: Pharmacological characterization of CGP 12177 at the human beta(2)-adrenoceptor.
abstract: 1 It has recently been reported that CGP 12177 can act as an agonist at a novel secondary site within the human beta(1)-adrenoceptor. The aim of this study was to undertake a detailed pharmacological study of the effects of CGP 12177 on the human beta(2)-adrenoceptor. 2 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 beta(2)-adrenoceptor. These CGP-induced responses were antagonized by the beta(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). 3 CGP 12177 was also able to antagonize both cyclic AMP and reporter gene responses to more efficacious beta(2)-agonists with similar log K(D) values (e.g. -9.57+/-0.15 and -10.04+/-0.096 respectively with salbutamol as agonist). 4 (3)H-CGP 12177 binding to beta(2)-adrenoceptors in intact CHO-beta(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(1/2) for dissociation=65 min). However, studies with a Green Fluorescent Protein (GFP)-tagged beta(2)-adrenoceptor indicated that CGP 12177 does not stimulate beta(2)-adrenoceptor internalization. 5 This study demonstrates that CGP 12177 is a high affinity partial agonist of both cAMP accumulation and CRE-mediated gene transcription at the human beta(2)-adrenoceptor. It provides no evidence that CGP 12177 can discriminate a secondary site on the beta(2)-adrenoceptor analogous to that observed for the human beta(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 beta(2)-adrenoceptor, coupled with its long duration of action, offers a potential lead for drug development for the treatment of chronic inflammatory airway diseases.
authors.affiliation: Institute of Cell Signalling, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH.
authors.forename: Jillian G
authors.initials: JG
authors.lastname: Baker
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hill
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000469:Alkaline Phosphatase; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis / Q000235:genetics; D058851:GPI-Linked Proteins; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D011412:Propanolamines / Q000494:pharmacology*; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D011412:Propanolamines; D000242:Cyclic AMP; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental; C033394:CGP 12177