SwePub
Sök i LIBRIS databas

  Extended search

onr:"swepub:oai:lup.lub.lu.se:7cd849ef-d493-44fc-9086-768fa61351ca"
 

Search: onr:"swepub:oai:lup.lub.lu.se:7cd849ef-d493-44fc-9086-768fa61351ca" > Extent of salmetero...

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Extent of salmeterol-mediated reassertion of relaxation in guinea-pig trachea pretreated with aliphatic side chain structural analogues

Bergendal, A (author)
Linden, A (author)
Skoogh, B E (author)
show more...
Gerspacher, M (author)
Anderson, G P (author)
Löfdahl, Claes-Göran (author)
Lund University,Lunds universitet,Lungmedicin, allergologi och palliativ medicin,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Respiratory Medicine, Allergology, and Palliative Medicine,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
show less...
 (creator_code:org_t)
1996
1996
English.
In: British Journal of Pharmacology. - 1476-5381. ; 117:6, s. 1009-1015
  • Journal article (peer-reviewed)
Abstract Subject headings
Close  
  • 1. Salmeterol is a potent, selective and long acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth muscle. Reassertion relaxation refers to the capacity of salmeterol to cause repeated functional antagonism of induced contraction when airway smooth muscle is intermittently exposed to, then washed free from, beta-adrenoceptor antagonists such as sotalol. The mechanism(s) underlying reassertion relaxation are unknown but may relate to high affinity binding of the long aliphatic side chain of salmeterol to an accessory site, distinct from the agonist recognition site, in or near the beta 2-adrenoceptor (exosite binding hypothesis). 2. In order to test the exosite hypothesis, three pure analogues of salmeterol, each exactly preserving the molecular structure of the aliphatic side chain but with zero or low efficacy at the beta 2-adrenoceptor were synthesized. The effect of pre-incubating guinea-pig tracheal smooth muscle with these analogues on salmeterol-induced reassertion relaxation was determined. 3. Computer Assisted Molecular Modelling of these molecules revealed that each of them exactly preserved the low energy linear conformation of the aliphatic side chain of salmeterol. Measurement of lipophilicity (octanol:water partition coefficient; log P) and direct partition into synthetic membranes (membrane partition coefficient; Kpmem) showed that all compounds had high affinity for lipids and membranes. In particular the biophysical properties of CGP 59162 (log P 1.89, Kpmem 16500) were very similar to salmeterol (log P 1.73, Kpmem 16800). 4. Two of the analogues, CGP 54103 and D 2543 (1 microM), which are structural mimics of the side chain of salmeterol, differing slightly in their length, did not prevent either the initial relaxation induced by salmeterol (0.1 microM) or the reassertion relaxation; however, it was not possible to determine whether either of these molecules occupied the beta 2-adrenoceptor. 5. The third analogue, CGP 59162, which has the substituents on the active saligenin head group of salmeterol in transposed positions, itself exerted a weak beta 2-adrenoceptor-mediated relaxation antagonized by ICI 118551 (beta 2-selective antagonist) but not CGP 20712 (beta 1-selective antagonist) and, at higher concentrations CGP 59162 caused reassertion relaxation suggesting that it may occupy and activate the beta 2-adrenoceptor in a manner analogous to salmeterol. 6. CGP 59162, at concentrations up to ten fold molar excess, did not prevent or reduce salmeterol-induced reassertion relaxation. 7. In conclusion these data are not consistent with the existence of a distinct 'exosite' recognising the aliphatic side chain of salmeterol mediating reassertion.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Keyword

fl-Adrenoceptor agonists
salmeterol
salmeterol analogues
airway smooth muscle relaxation
duration of action
reassertion
exosite

Publication and Content Type

art (subject category)
ref (subject category)

Find in a library

To the university's database

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Find more in SwePub

By the author/editor
Bergendal, A
Linden, A
Skoogh, B E
Gerspacher, M
Anderson, G P
Löfdahl, Claes-G ...
About the subject
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Basic Medicine
and Pharmacology and ...
Articles in the publication
British Journal ...
By the university
Lund University

Search outside SwePub

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view