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Biological actions ...
Biological actions of formoterol isomers
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- Handley, Dean A. (author)
- Sepracor Inc, Marlborough, MA, USA
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- Senanayake, Chris H (author)
- Sepracor Inc, Marlborough, MA, USA
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- Dutczak, William (author)
- Sepracor Inc, Marlborough, MA, USA
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- Benovic, Jeffrey L (author)
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA
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- Walle, Thomas (author)
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA
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- Penn, Raymond B. (author)
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA
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- Wilkinson, H. Scott (author)
- Sepracor Inc, Marlborough, MA, USA
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- Tanoury, Gerald J. (author)
- Sepracor Inc, Marlborough, MA, USA
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- Andersson, Rolf, 1943- (author)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Johansson, Fredrik (author)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Morley, John (author)
- Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy, Guys, King's and St Thomas' School of Medicine, Denmark Hill, London, UK
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(creator_code:org_t)
- Elsevier BV, 2002
- 2002
- English.
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In: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1094-5539 .- 1522-9629. ; 15:2, s. 135-145
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.
Keyword
- ß2 adrenoceptor
- Asthma
- Formoterol
- Isomers
- Tracheal tissue
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Handley, Dean A.
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Senanayake, Chri ...
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Dutczak, William
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Benovic, Jeffrey ...
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Walle, Thomas
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Penn, Raymond B.
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Wilkinson, H. Sc ...
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Tanoury, Gerald ...
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Andersson, Rolf, ...
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Johansson, Fredr ...
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Morley, John
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- Articles in the publication
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Pulmonary Pharma ...
- By the university
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Linköping University