Biological Actions of Formoterol Isomers

Handley, Dean A.; Senanayake, Chris H.; Dutczak, William; Benovic, Jeffrey L.; Walle, Thomas; Penn, Raymond B.; Wilkinson, H. Scott; Tanoury, Gerald J.; Andersson, Rolf G. G.; Johansson, Fredrik; Morley, John E.

doi:10.1006/pupt.2001.0327

Cited by 49 publications

(37 citation statements)

References 28 publications

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“…Clinical and animal data suggest that (R,R)-and racemic formoterol have a similar potency to promote airway relaxation (7)(8)(9). However, others studies suggest that (S,S)-formoterol may not be biologically inactive as previously thought, but may reduce the relaxant efficacy of the racemic mixture (10). In addition, (S,S)-formoterol may promote inflammation (11).…”

mentioning

confidence: 97%

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Delmotte

Sanderson

2010

Am J Respir Cell Mol Biol

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Formoterol, a long-acting b 2 -receptor agonist, is used to relieve bronchial constriction. However, formoterol is often a racemic formulation, and contains both (R,R)-and (S,S)-enantiomers. Because the activity of each isomer is poorly defined, the mechanisms by which formoterol relaxes smooth muscle cells (SMCs) of intrapulmonary airways are not well understood. Consequently, we compared the effects of (S,S)-, (R,R)-, and racemic formoterol, as well as (R)-albuterol, on the contraction and Ca 21 signaling of airway SMCs in mouse lung slices with phase-contrast and confocal microscopy. Small airways were contracted with methacholine and the associated SMCs displayed sustained Ca 21 oscillations and an increase in Ca 21 sensitivity. These contracted airways displayed a substantial, concentration-dependent relaxation in response to (R,R)-formoterol. Racemic formoterol had a similar potency as (R,R)-formoterol for relaxing airways. By contrast, (S,S)-formoterol only induced a small relaxation. In conjunction with relaxation, (R,R)-and racemic formoterol stopped and decreased the methacholineinduced Ca 21 oscillations and Ca 21 sensitivity of the SMCs, respectively, whereas (S,S)-formoterol only decreased the Ca 21 sensitivity. In these studies, (R,R)-and racemic formoterol had a similar, but much greater, potency than (R)-albuterol for relaxing mice airways. This action was quickly initiated at high concentrations by decreasing the frequency of Ca 21 oscillations, but was more usually mediated at lower concentrations by decreasing the Ca 21 sensitivity of the SMCs.

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confidence: 97%

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Delmotte

Sanderson

2010

Am J Respir Cell Mol Biol

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“…18) Concerning the relaxation efficacy in isolated trachea strips, (Ϫ)-SPFF exerted a more potent tracheal relaxing ef- .08, respectively, with no significant difference from each other in the present study, and they all fell into the range of reported pA 2 values for ICI-118551 antagonizing on the known b 2 -selective agonists fenoterol 19) and salbutamol. 20) Furthermore, the slope factor of the Schild plot for ICI-118551 versus (Ϫ)-, (ϩ)-SPFF and (Ϯ)-SPFF was not significantly different from unity (close to 1.0) , suggesting that the relaxing effect of (Ϫ)-and (ϩ)-enantiomers on guinea pig isolated tracheal muscle was mediated principally via b 2 -adrenoceptor as racemic SPFF and other b 2 -adrenoceptor agonists had been.…”

Section: Discussionmentioning

confidence: 40%

“…31) Regarding the duration of action in inhibiting C L , both (Ϫ)-and (ϩ)-SPFF displayed a tendency to decrease slightly in 4 h after intraduodenal administration, which implied that the individual enantiomer might have a shorter duration than racemic SPFF. Whether or not the shorter duration for both enantiomers is due to the relatively faster rate of metabolism like (Ϫ)-R-salbutemol 32) and (R,R)-formoterol 18) has not yet been established. Investigations are underway in our laboratory to distinguish the metabolism of racemic SPFF and its enantiomers.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Hao

Zhang

et al. 2008

Biological & Pharmaceutical Bulletin

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b 2 -Adrenoceptor agonists, the most effective bronchodilator, have long been widely used in symptomatic therapy of asthma. A variety of b 2 -adrenoceptor agonists are currently available, such as salbutamol, terbutaline, salmeterol, formoterol and procaterol. The majority of b 2 -adrenoceptor agonists possess chiral center(s) (asymmetric carbon atom) in their structures; therefore, they exist as pair(s) of enantiomers.1) Based on the conformational stereochemistry and pharmacokinetic parameters, enantiomers can vary greatly in their pharmacological effects on target tissue(s).2) Except for levalbuterol, most available b 2 -adrenoceptor agonists are a racemic mixture of equimolar (R)-and (S)-enantiomer. Against this background, separation of enantiomers is a practice increasing in popularity, since a single optical isomer may represent a safer and more efficacious alternative than its corresponding racemate.3) 2-(4-Amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) is synthesized and exploited by the drug synthesis laboratory of Shenyang Pharmaceutical University as a novel b 2 -adrenoceptor agonist. Gan et al. 4) has found that bronchodilator effects of racemic SPFF on isolated guinea pig trachea strips with or without precontraction of bronchoconstrictors (histamine and acetylcholine) were more potent than isoprenaline. Moreover, it was confirmed that the bronchodilator effect of racemic SPFF was due to the activation of b 2 -adrenoceptor because this effect was easily antagonized by a specific b 2 -adrenoceptor antagonist, ICI-118551 (pA 2 ϭ8.90Ϯ0.01). Furthermore, the positive chronotropic effect of SPFF on isolatd guinea pig left atria (pD 2 ϭ5.41Ϯ0.38) was much weaker than that of isoprenaline (pD 2 ϭ8.75Ϯ0.24). A radioligand binding experiment using guinea pig lung and cardiac ventricle as b 2 and b 1 adrenoceptor sources, respectively, also demonstrated that racemic SPFF possesses high affinity and selectivity to b 2 -adrenoceptor. The protective effect of racemic SPFF on bronchospasm induced by bronchoconstrictor aerosol in guinea pig in vivo was 6 times more potent than that of sulbutamol, and the Konzett and Rösler experiment performed in anesthetized rabbits showed that racemic SPFF exerted action of longer duration than sulbutamol did. In the present study we compared the pharmacological effects of racemic SPFF with its individual enantiomers on bronchodilating action and potency in guinea pigs. MATERIALS AND METHODS Chemicals and Drugs

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“…However, the bronchoprotection afforded by shortacting drugs persist for less than 3 -4 h, so that it becomes necessary to use these drugs regularly to achieve symptomatic control. β 2 selective agonists with a longer duration of action have been introduced into therapy [7,10].…”

Section: Bronchodilatorsmentioning

confidence: 99%

“…Mass spectroscopy analysis of individual peaks allowed identification of the fragments of formoterol sulphate. Separation of the constituents of culture medium by reversed phase HPLC produced a major peak with a retention time of 12 min [10].…”

Section: Clinical Studiesmentioning

confidence: 99%

Arformoterol Tartrate: A Review of Pharmacology, Analysis and Clinical Studies

Pahwa¹,

Soni²,

Sharma³

et al. 2011

Trop. J. Pharm Res

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Biological Actions of Formoterol Isomers

Cited by 49 publications

References 28 publications

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Arformoterol Tartrate: A Review of Pharmacology, Analysis and Clinical Studies

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Biological Actions of Formoterol Isomers

Cited by 49 publications

References 28 publications

Effects of Formoterol on Contraction and Ca2+ Signaling of Mouse Airway Smooth Muscle Cells

Effects of Formoterol on Contraction and Ca2+ Signaling of Mouse Airway Smooth Muscle Cells

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Arformoterol Tartrate: A Review of Pharmacology, Analysis and Clinical Studies

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Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells