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The design, synthesis and pharmacological characterization of novel β 2 ‐adrenoceptor antagonists
Author(s) -
Hothersall J Daniel,
Black James,
Caddick Stephen,
Vinter Jeremy G,
Tinker Andrew,
Baker James R
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01269.x
Subject(s) - antagonist , partial agonist , agonist , pharmacology , chemistry , intrinsic activity , inverse agonist , potency , receptor , ligand (biochemistry) , enantiomer , stereochemistry , in vitro , biology , biochemistry
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.