The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.

Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds.

Interaction between adenosine and allergen or compound 48/80 on lung parenchymal strips from actively sensitized Brown Norway rats.

We have investigated the effect of mast cell activation induced by immunological and non-immunological stimuli on the sensitivity to adenosine of parenchymal strips prepared from lungs removed from Brown Norway (BN) rats actively sensitized to ovalbumin. Strips responded to ovalbumin with a biphasic contractile response. Responses to adenosine were markedly increased 30 min after ovalbumin.

Antagonist pharmacology of adenosine A2B receptors from rat, guinea pig and dog.

We have sought evidence for species differences between adenosine A2B receptors by comparing the potencies of eight adenosine receptor antagonists, representing four different chemical classes, at the native adenosine A2B receptors which mediate relaxation of smooth muscle from rat colon, guinea pig aorta and dog saphenous vein. In all three assays, the antagonists caused parallel rightward shifts in the concentration-response curves to NECA and there was no depression of the maximum responses. There were highly significant correlations between the pKB values on each of the three receptors.