دورية أكاديمية
أعرض في EDS

Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists.

التفاصيل البيبلوغرافية
العنوان: Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists.
المؤلفون: Sykes DA; Novartis Institutes for Biomedical Research, West Sussex, UK., Charlton SJ
المصدر: British journal of pharmacology [Br J Pharmacol] 2012 Apr; Vol. 165 (8), pp. 2672-83.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.
مواضيع طبية MeSH: Adrenergic beta-2 Receptor Agonists/*metabolism , Receptors, Adrenergic, beta-2/*metabolism, Administration, Inhalation ; Adrenergic beta-Antagonists/metabolism ; Animals ; Binding, Competitive ; CHO Cells ; Cell Membrane/metabolism ; Cricetinae ; Cricetulus ; Dihydroalprenolol/analogs & derivatives ; Dihydroalprenolol/metabolism ; Humans ; Iodocyanopindolol/metabolism ; Kinetics ; Radioligand Assay
مستخلص: Background and Purpose: β(2) -Adrenoceptor agonists are important bronchodilators used for the treatment of chronic obstructive pulmonary disease and asthma. Clinical data on β(2) -adrenoceptor agonists show a range of onset and duration of action. We have investigated whether the receptor binding kinetics of β(2) -adrenoceptor agonists can explain their observed onset of action and duration of effect in the clinic.
Experimental Approach: [(3) H]-DHA was used to label β(2) -adrenoceptors expressed in CHO-cell membranes (K(d) of 0.084 nM). Competition kinetic experiments were performed in the presence of unlabelled β(2) agonists at 37°C in HBSS containing GTP. To determine the kinetic parameters, three concentrations (10, 3 and 1 ×K(i) ) of the unlabelled compound were employed against a fixed concentration of [(3) H]-DHA (0.6 nM).
Key Results: The clinically used β(2) -adrenoceptor agonists exhibited a range of association and dissociation rates. The kinetic K(d) and the competition K(i) values of the eight β(2) -adrenoceptor agonists examined were strongly correlated, suggesting that the method had produced accurate k(off) and k(on) rates. The kinetic on-rate was highly correlated with equilibrium binding affinity.
Conclusions and Implications: Although the β(2) -adrenoceptor agonists displayed a range of kinetic rate parameters, simulations at relevant drug concentrations suggest that receptor kinetics do not play an important role in determining onset of action in the clinic. In addition, it is unlikely that receptor kinetics exert an important influence on the duration of action of these agonists, as indacaterol (once daily dosing) had a shorter residency time at the receptor than salmeterol (twice daily dosing).
(© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
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المشرفين على المادة: 0 (Adrenergic beta-2 Receptor Agonists)
0 (Adrenergic beta-Antagonists)
0 (Receptors, Adrenergic, beta-2)
121864-88-8 (1-(4,6-propyl)dihydroalprenolol)
60106-89-0 (Dihydroalprenolol)
83498-72-0 (Iodocyanopindolol)
تواريخ الأحداث: Date Created: 20110903 Date Completed: 20120727 Latest Revision: 20211020
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3423252
DOI: 10.1111/j.1476-5381.2011.01639.x
PMID: 21883146
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5381
DOI:10.1111/j.1476-5381.2011.01639.x