The design, synthesis and pharmacological characterization of novel β 2-adrenoceptor antagonists

Abstract

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH A range of pharmacological assays was used to assess potency, affinity, selectivity (β 2-adrenoceptor vs. β 1-adrenoceptor) and efficacy. KEY 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 AND IMPLICATIONS 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. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.