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The design, synthesis and pharmacological characterization of novel beta(2)-adrenoceptor antagonists

Hothersall, JD; Black, J; Caddick, S; Vinter, JG; Tinker, A; Baker, JR; (2011) The design, synthesis and pharmacological characterization of novel beta(2)-adrenoceptor antagonists. BRIT J PHARMACOL , 164 (2) 317 - 331. 10.1111/j.1476-5381.2011.01269.x.

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Abstract

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

Type: Article
Title: The design, synthesis and pharmacological characterization of novel beta(2)-adrenoceptor antagonists
DOI: 10.1111/j.1476-5381.2011.01269.x
Keywords: adrenoceptor, antagonist, cell signalling, PROTEIN-COUPLED RECEPTOR, BETA-ADRENOCEPTOR ANTAGONISTS, CHRONIC HEART-FAILURE, GUINEA-PIG TRACHEA, BIOLOGICAL-ACTIVITY, CLINICAL-OUTCOMES, CRYSTAL-STRUCTURE, INVERSE AGONISTS, PROVIDE EVIDENCE, PA2 VALUES
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > VP Innovation and Enterprise
URI: http://discovery.ucl.ac.uk/id/eprint/1321708
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