title: The design, synthesis and pharmacological characterization of novel β₂-adrenoceptor antagonists.
abstract: OBJECTIVE
  Selective and potent antagonists for the β(2) -adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology.
  
  
  METHODS
  A range of pharmacological assays was used to assess potency, affinity, selectivity (β(2) -adrenoceptor vs. β(1) -adrenoceptor) and efficacy.
  
  
  RESULTS
  Ten novel compounds were identified but none had as high affinity as the prototypical β(2) -adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for β(2) -adrenoceptors. Most of the ligands were inverse agonists for β(2) -adrenoceptor-cAMP signalling, although one (5217377) was a partial agonist and another a neutral antagonist (7929193). None of the ligands were efficacious with regard to β(2) -adrenoceptor-β-arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the β(2) -adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour.
  
  
  CONCLUSIONS
  In terms of improving on the pharmacology of the ligand ICI-118,551, one of the compounds was more selective (racemic JB-175), while one was a neutral antagonist (7929193), although none had as high an affinity. The results substantiate the notion that β-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology.
authors.affiliation: Department of Medicine, University College London, London, UK.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Hothersall
authors.forename: James
authors.initials: J
authors.lastname: Black
authors.forename: Stephen
authors.initials: S
authors.lastname: Caddick
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Vinter
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D000242:Cyclic AMP; D015195:Drug Design; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D011412:Propanolamines / Q000494:pharmacology*; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D000242:Cyclic AMP