Formoterol: Pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective β2-adrenoceptor agonist bronchodilator

doi:10.1016/0024-3205(93)90729-M

Life Sciences

Volume 52, Issue 26, 1993, Pages 2145-2160

https://doi.org/10.1016/0024-3205(93)90729-M Get rights and content

Abstract

Formoterol is an innovative, highly potent, β₂-adrenoceptor-selective agonist combining the clinical advantages of rapid onset of action with a duration of action in excess of 12 h. In vitro, formoterol is a potent airway smooth muscle relaxant with high efficacy, and very high affinity and selectivity for the β₂-adrenoceptor. Formoterol appears to be retained in airway smooth muscle for extended periods since its relaxant effect on human airway smooth muscle is resistant to repeated washing and formoterol displays ‘reassertion’ of relaxation after washout of a β-adrenoceptor antagonist. A model based on the diffusion microkinetics of formoterol into the plasmalemma lipid bilayer is proposed as a basis for these properties.

In addition to the release of pro-inflammatory mediators from cells such as the mast cell, several other disease processes probably occur in asthma. Leukocytes, notably eosinophils, adhere to the vascular endothelium and emigrate into airway tissues, which may be damaged by these cells if they are activated to release mediators or their granular contents. Plasma and its component proteins are extravasated from the bronchial microcirculation. Formoterol has been demonstrated to potently inhibit these cells and processes in experimental test systems. Continuing clinical research involving histological examination of tissue reactions may allow a more complete determination of the effects of formoterol on inflammatory processes in humans and the clinical relevance of any such effects.

References (58)

A-B Jeppsson et al.
On the predictive value of experiments in vitro in the evaluation of the effect duration of bronchodilator drugs for local administration
Pulm Pharmacol
(1989)
K Tokuyama et al.
Inhaled formoterol inhibits histamine induced airflow obstruction and airway microvascular leakage
Eur J Pharmacol
(1991)
RW Fuller et al.
Human alveolar macrophage activation: inhibition by forskolin but not beta-adrenoceptor stimulation of phosphodiesterase inhibition
Pulm Pharmacol
(1988)
LG Herbette et al.
Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol, nimodipine and amiodarone
J Mol Cell Cardiol
(1988)
PRM Hekking et al.
Efficacy and tolerability of inhaled formoterol compared with inhaled salbutamol over three months
R Pauwels
Rate of onset and duration of action of beta-2-agonists: comparison of inhaled formoterol with salbutamol
T. Tasaka
Formoterol (Atock): a new orally active and selective beta 2 receptor stimulant
Drugs Today
(1986)
N Decker et al.
Effects of n-aralkyl substitution of the beta-agonist on alpha- and beta-adrenoceptor subtypes: pharmacological studies and binding assays
J Pharm Pharmcol
(1982)
Advenier C, Zhang Y, Naline E et al. Relaxant effects and long duration of action of formoterol on the human isolated...
H Lemoine et al.
Increased muscarinic prestimulation of guinea-pig tracheal strips decreases potency and intrinsic activity of synthetic beta-2 sympathomimetics. Comparison of relaxation with receptor binding and adenylate cyclase stimulation
Naunyn Schmied Arch Pharmacol
(1991)

TP Kenakin

Pharmacological analysis of drug-receptor interaction

(1987)

J Offermeier et al.

The antagonism between cholinomimetic agonists and beta-adrenoceptor stimulants. The difference between functional and metaffinoid antagonism

Eur J Pharmacol

(1973)

TJ Torphy et al.

Inhibitory effect of methacholine on drug-induced relaxation, cyclic AMP accumulation, and cyclic AMP-dependent protein kinase activation in canine tracheal smooth muscle

J Pharmacol Exp Ther

(1985)

C Davis et al.

Beta-adrenoceptors in human lung, bronchus and lymphocytes

Br J Clin Pharmacol

(1980)

IG Dougall et al.

Estimation of the efficacy and affinity of the β₂-adrenoceptor agonist salmeterol in guinea-pig trachea

Br J Pharmacol

(1991)

M Johnson

Salmeterol: a novel drug for the treatment of asthma

B Raffestin et al.

Response and sensitivity of isolated human pulmonary muscle preparations to pharmacological agents

J Pharmacol Exp Ther

(1985)

C Raper et al.

Salbutamol: agonistic and antagonistic activity at beta-adrenoceptor sites

J Pharm Pharmacol

(1976)

RS Kent et al.

A quantitative analysis of beta-adrenergic receptor interactions: resolution of high and low affinity state of the receptor by computer modeling of ligand binding data

Mol Pharmacol

(1980)

FJ Roux et al.

Biological potency and receptor binding characteristics of formoterol and salmeterol

Am Rev Respir Dis

(1992)

H Meurs et al.

Cross-talk between receptor mechanisms in relation to airway obstruction

Eur Respir J

(1991)

RGM Van Amsterdam et al.

Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists

Am Rev Respir Dis

(1990)

P Arvidsson et al.

Inhaled formoterol during one year in asthma: a comparison with salbutamol

Eur Respir J

(1991)

AT Nials et al.

Salmeterol and formoterol: are they both long acting beta-2 adrenoceptor agonists?

Br J Pharmacol

(1990)

A Lindén et al.

High concentrations of formoterol and salmeterol in the guinea-pig trachea — reassertion of smooth muscle relaxation after beta-blockade followed by washout

Am Rev Respir Dis

(1991)

C-G Lofdahl

Basic pharmacology of new long acting sympathomimetics

Lung

(1990)

RA Coleman et al.

The interaction between salmeterol and beta-adrenoceptor blocking drugs on the guinea-pig trachea in vitro

Am Rev Respir Dis

(1992)

C-G Lofdahl et al.

Formoterol fumerate, a new beta-adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration

Allergy

(1989)

D Faulds et al.

Formoterol. A review of its pharmacological properties and therapeutic potential in obstructive airways disease

Drugs

(1991)

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Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.
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Effect of a single day of increased as-needed budesonide–formoterol use on short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study
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In mild asthma, as-needed budesonide–formoterol reduces long-term exacerbation risk compared with as-needed short-acting β₂-agonist (SABA), with a similar or increased reduction versus maintenance with budesonide plus as-needed SABA, despite a lower budesonide dose. In this post-hoc analysis of the SYmbicort Given as needed in Mild Asthma (SYGMA) 1 study, we investigated the short-term risk of severe exacerbations after a single day with various levels of reliever use.
SYGMA 1 was a 52-week, double-blind, randomised, controlled, phase 3 trial, in which patients aged 12 years or older with mild asthma were randomly assigned (1:1:1) to placebo twice daily plus as-needed terbutaline 0·5 mg, placebo twice daily plus as-needed budesonide–formoterol 200–6 μg, or budesonide 200 μg twice daily plus as-needed terbutaline (ie, budesonide maintenance group). In this post-hoc analysis, we assessed the frequency of reliever use and the risk of a severe exacerbation in the 21 days after first use of more than two, four, six, or eight reliever inhalations in 24 h. SYGMA 1 is registered with ClinicalTrials.gov, NCT02149199, and is now complete.
Of 5721 patients enrolled in SYGMA 1, 3849 were randomly assigned to as-needed terbutaline (n=1280), as-needed budesonide–formoterol (n=1279), or budesonide maintenance (n=1290), of whom 3836 had evaluable data (n=1277 as-needed terbutaline, n=1277 as needed budesonide–formoterol, and n=1282 budesonide maintenance). Median reliever use was 0·32 (IQR 0·08–0·91) inhalations per day for the as-needed terbutaline group, 0·29 (0·07–0·72) for the as-needed budesonide–formoterol group, and 0·16 (0·04–0·52) for the budesonide maintenance group. Compared with as-needed terbutaline, after adjustment for age, sex, randomly assigned treatment, pre-study treatment group, baseline % predicted post-bronchodilator FEV₁, and severe exacerbation in the 12 months before enrolment in the study, the hazard ratio (HR) for severe exacerbation in the 21 days after a single day with more than two as-needed inhalations was 0·27 (95% CI 0·12–0·58; p=0·0008) with as-needed budesonide–formoterol and 0·39 (0·19–0·79; p=0·0091) with budesonide maintenance; after a single day of more than four as-needed inhalations the HR was 0·24 (0·10–0·62; p=0·0030) with as-needed budesonide–formoterol and 0·30 (0·13–0·72; p=0·0065) with budesonide maintenance; and after a single day of more than six as-needed inhalations the HR was 0·14 (0·02–1·06; p=0·057) with as-needed budesonide–formoterol and 0·43 (0·14–1·26; p=0·12) with budesonide maintenance. HRs were not calculated for more than eight as-needed inhalations due to the small number of events.
In mild asthma, as-needed budesonide–formoterol reduces the short-term risk of severe exacerbations after a single day of higher use (more than two as-needed inhalations), even when overall use is infrequent. Use of an anti-inflammatory reliever might reduce the risk of short-term severe exacerbations by the timely provision of increased doses of as-needed inhaled corticosteroids and formoterol when symptoms occur. These findings should be further assessed in prospective randomised clinical trials.
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Diastereoselective hydrogenation of Formoterol intermediate over M(Ir, Pd, Pt, Rh, Ru)/BEA zeolite catalysts
2020, Catalysis Today
Citation Excerpt :
We recently reviewed the chemo- and diastereoselective hydrogenation of a CO group in the presence of a CC double bond, with a particular emphasis on the stereoselective C(15) synthesis from the PGF2α analogue structure [28]. Formoterol (Foradil®) (N-[2-hydroxy-5-[(RS)-1-hydroxy-2-[(RS)-2-(4-metoxy phenyl)-1-methylethylamino] ethyl]phenyl]formamide), is a long acting, potent β2-agonist, used as a bronchodilator in the therapy of asthma and chronic bronchitis [29]. As Cloprostenol, Formoterol is currently marketed as a racemate even it has been shown that pure enantiomers of chiral drugs are more potent or have fewer side effects compared to their racemates [30–32].
The chemo- and diastereoselective hydrogenation of Formoterol intermediate (2-[N-benzoyl-N-[(R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-4’-benzoyloxy-3’ nitro acetophenone) (3)) has been investigated on M(Ir, Pd, Pt, Rh, Ru)/BEA zeolite catalysts. Catalytic performances were well correlated with the catalysts characteristics. Both the chemo- and diastereoselectivity were influenced by the metal dispersion and its reduction degree. The obtained results also underlined the essential role of H-BEA as a selectivity-promoting support.
Formoterol counteracts the inhibitory effect of cigarette smoke on glucocorticoid-induced leucine zipper (GILZ) transactivation in human bronchial smooth muscle cells
2019, European Journal of Pharmacology
Cigarette smokers with asthma and chronic obstructive pulmonary disease (COPD) are less responsive to glucocorticoids (GCs). The anti-inflammatory action of GCs depends also on their ability to transactivate genes such as GC-induced leucine zipper (GILZ). We investigated the effects of aqueous cigarette smoke extract (CSE) on GILZ transactivation evoked by 17-beclomethasone monopropionate (BMP) or fluticasone propionate (FP) in the presence or absence of the long acting β2-adrenoceptor agonist (LABA) bronchodilator formoterol or salmeterol in human primary cultures of human bronchial smooth muscle cells (HBSMC). We monitored GC receptor Ser211 phosphorylation by western blot analysis and GC receptor nuclear translocation by immunostaining followed high-content imaging analysis. BMP, as well as FP, induced GILZ expression in a concentration-dependent manner (EC₅₀ of 0.87 and 0.16 nM respectively). Pre-incubation with CSE inhibited GC-evoked GILZ transactivation (>50%), GC receptor Ser211 phosphorylation and nuclear translocation. Both formoterol and salmeterol counteracted the effect of CSE on GC-induced GILZ expression but not on nuclear translocation or phosphorylation. The effect of formoterol was mimicked by the cAMP-elevating agent forskolin and blocked by ICI 118,551, a selective β2-adrenoceptor antagonist. Pre-incubation with TNF-α also reduced GC-evoked GILZ transactivation but was not counteracted by formoterol undercovering a different responsiveness to LABAs of TNF-α in comparison to CSE.
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Formoterol: Pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective β2-adrenoceptor agonist bronchodilator

Abstract

Pulm Pharmacol

Eur J Pharmacol

Pulm Pharmacol

J Mol Cell Cardiol

Efficacy and tolerability of inhaled formoterol compared with inhaled salbutamol over three months

Rate of onset and duration of action of beta-2-agonists: comparison of inhaled formoterol with salbutamol

Formoterol (Atock): a new orally active and selective beta 2 receptor stimulant

Drugs Today

Effects of n-aralkyl substitution of the beta-agonist on alpha- and beta-adrenoceptor subtypes: pharmacological studies and binding assays

J Pharm Pharmcol

Increased muscarinic prestimulation of guinea-pig tracheal strips decreases potency and intrinsic activity of synthetic beta-2 sympathomimetics. Comparison of relaxation with receptor binding and adenylate cyclase stimulation

Naunyn Schmied Arch Pharmacol

Pharmacological analysis of drug-receptor interaction

The antagonism between cholinomimetic agonists and beta-adrenoceptor stimulants. The difference between functional and metaffinoid antagonism

Eur J Pharmacol

Inhibitory effect of methacholine on drug-induced relaxation, cyclic AMP accumulation, and cyclic AMP-dependent protein kinase activation in canine tracheal smooth muscle

J Pharmacol Exp Ther

Beta-adrenoceptors in human lung, bronchus and lymphocytes

Br J Clin Pharmacol

Estimation of the efficacy and affinity of the β2-adrenoceptor agonist salmeterol in guinea-pig trachea

Br J Pharmacol

Salmeterol: a novel drug for the treatment of asthma

Response and sensitivity of isolated human pulmonary muscle preparations to pharmacological agents

J Pharmacol Exp Ther

Salbutamol: agonistic and antagonistic activity at beta-adrenoceptor sites

J Pharm Pharmacol

A quantitative analysis of beta-adrenergic receptor interactions: resolution of high and low affinity state of the receptor by computer modeling of ligand binding data

Mol Pharmacol

Biological potency and receptor binding characteristics of formoterol and salmeterol

Am Rev Respir Dis

Cross-talk between receptor mechanisms in relation to airway obstruction

Eur Respir J

Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists

Am Rev Respir Dis

Inhaled formoterol during one year in asthma: a comparison with salbutamol

Eur Respir J

Salmeterol and formoterol: are they both long acting beta-2 adrenoceptor agonists?

Br J Pharmacol

High concentrations of formoterol and salmeterol in the guinea-pig trachea — reassertion of smooth muscle relaxation after beta-blockade followed by washout

Am Rev Respir Dis

Basic pharmacology of new long acting sympathomimetics

Lung

The interaction between salmeterol and beta-adrenoceptor blocking drugs on the guinea-pig trachea in vitro

Am Rev Respir Dis

Formoterol fumerate, a new beta-adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration

Allergy

Formoterol. A review of its pharmacological properties and therapeutic potential in obstructive airways disease

Drugs

Formoterol: Pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective β₂-adrenoceptor agonist bronchodilator

Estimation of the efficacy and affinity of the β₂-adrenoceptor agonist salmeterol in guinea-pig trachea