Mechanisms of Action ofβ2-Adrenoceptor Agonists

Johnson, Malcolm

doi:10.1002/9780470694923.ch30

Cited by 17 publications

(22 citation statements)

References 27 publications

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“…In summary, these data support at biological level the hypothesis that the combination of the two types of drugs, long-acting b 2 -adrenoceptor agonists and inhaled steroids, not only allows a better clinical control of asthma, but may also help to prevent longterm deterioration of lung function [1]. Although the concentrations of drugs used in vitro in this paper are similar to those found in peripheral lung tissue after 50 mg inhaled dose of salmeterol [35], the clinical importance of the experimental observations reported here deserves further investigation.…”

Section: Discussionsupporting

confidence: 53%

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

Silvestri¹,

Fregonese²,

Sabatini³

et al. 2001

Eur Respir J

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b 2 -adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma.Since fibroblasts express b 2 -adrenoreceptors, the effects of different concentrations (0.1 -100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FPzS) on lung fibroblast proliferation and adhesion molecule expression were evaluated.Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-3 H] thymidine ([ 3 H]TdR) uptake, four-fold higher than that of control cultures (p~0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1 -100 nM; pv0.05). No changes in bFGFinduced cell proliferation were observed in the presence of FP (0.1 -100 nM; pw0.05, all comparisons). In addition, the association FPzS did not improve the inhibitory activity of S alone (pw0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor-a (TNF-a) (p~0.0004), but not by interleukin-4 (IL-4) (pw0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (pw0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1 -100 nM; pv0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (pv0.01), but not on H-CAM expression (pw0.1).These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.

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Section: Discussionsupporting

confidence: 53%

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

Silvestri¹,

Fregonese²,

Sabatini³

et al. 2001

Eur Respir J

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“…After ligand binding to the active site of the receptor, the a-component of the associated G s -protein dissociates and activates adenylate cyclase, 125 leading to the production of intracellular cAMP and subsequent activation of protein kinase A (PKA), which then phosphorylates several intracellular regulatory proteins. 126 b 2 -Agonists may also influence gene transcription through a cAMP mechanism whereby there is increased translocation of the catalytic subunit of PKA to the nucleus and phosphorylation of CRE binding protein, enhancing its DNA-binding and transactivation effects. 127 More recently, it has been reported that activation of the b 2 AR can also lead to coupling to G i , resulting in stimulation of the ERK and p38 MAPK pathways.…”

Section: Mechanism Of Action Of B 2 -Agonistsmentioning

confidence: 99%

“…128 The mechanisms of action of the LABAs, salmeterol and formoterol, have been reported previously. 129,130 Briefly, salmeterol partitions into the cell membrane and diffuses laterally to the b 2 AR. The side chain of the molecule then binds to a discrete, hydrophobic region of the fourth transmembrane domain, the exo-site.…”

Section: Mechanism Of Action Of B 2 -Agonistsmentioning

confidence: 99%

Synthetic responses in airway smooth muscle

Howarth

Knox²,

Amrani³

et al. 2004

Journal of Allergy and Clinical Immunology

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147

105

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“…Based on structure-activity relationship studies with analogues of salmeterol (the most extensively documented member of this group), it has been proposed that the lipophilic side chain of salmeterol binds tightly to an 'exosite' at the interface between the β 2 -adrenoceptor and the lipid bilayer and that the oxygen in the middle of this molecule acts as a hinge that allows the saligenin head to pivot through the transmembrane domains of the receptor to engage and disengage the binding site rapidly [55] (Figure 2C). Although such an exosite still awaits experimental confirmation, it is of note that a similar bi/multivalency is well known to increase the affinity/'avidity' and long-lasting binding of antibodies and of many other biological interactions [56].…”

Section: Participation Of the Membrane In The Binding Processmentioning

confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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Mechanisms of Action ofβ2-Adrenoceptor Agonists

Cited by 17 publications

References 27 publications

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

Synthetic responses in airway smooth muscle

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

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