Document Detail

Pharmacogenetic characterization of indacaterol, a novel beta 2-adrenoceptor agonist.
MedLine Citation:
PMID:  19422388     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: Indacaterol is a novel beta(2)-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human beta(2)-adrenoceptor and in human primary airway smooth muscle (ASM) cells.
EXPERIMENTAL APPROACH: Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human beta(2)-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3',5'-cyclic-monophosphate production was used as an outcome measure.
KEY RESULTS: In both the low- and high-expression recombinant GEVT 'wild type' cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the beta(2)-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3',5'-cyclic-monophosphate in response to beta(2)-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.
CONCLUSIONS AND IMPLICATIONS: These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of beta(2)-adrenoceptors.
I Sayers; J Hawley; C E Stewart; C K Billington; A Henry; J R Leighton-Davies; S J Charlton; I P Hall
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-04-30
Journal Detail:
Title:  British journal of pharmacology     Volume:  158     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2010-05-20     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  277-86     Citation Subset:  IM    
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MeSH Terms
Adrenergic beta-2 Receptor Agonists*
CHO Cells
Cells, Cultured
Cyclic AMP / biosynthesis
Genetic Variation / drug effects
Indans / pharmacology*
Pharmacogenetics* / methods
Polymorphism, Single Nucleotide / drug effects,  genetics
Quinolones / pharmacology*
Receptors, Adrenergic, beta-2 / genetics*
Grant Support
G0400283//Medical Research Council; G0400910//Medical Research Council
Reg. No./Substance:
0/Adrenergic beta-2 Receptor Agonists; 0/Indans; 0/Quinolones; 0/Receptors, Adrenergic, beta-2; 0/indacaterol; E0399OZS9N/Cyclic AMP

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