The design, synthesis and pharmacological characterization of novel ??-adrenoceptor antagonists.

ABSTRACT: Selective and potent antagonists for the ?(2) -adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology.A range of pharmacological assays was used to assess potency, affinity, selectivity (?(2) -adrenoceptor vs. ?(1) -adrenoceptor) and efficacy.Ten novel compounds were identified but none had as high affinity as the prototypical ?(2) -adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for ?(2) -adrenoceptors. Most of the ligands were inverse agonists for ?(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 ?(2) -adrenoceptor-?-arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the ?(2) -adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour.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 ?-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology.

SUBMITTER: Hothersall JD 

PROVIDER: S-EPMC3174413 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature