Bronchospasmolytic agent 1

Bronchospasmolytic activity and adenosine receptor binding of some newer 1,3-dipropyl-8-phenyl substituted xanthine derivatives

The aldehyde derivatives of 1,3-dipropyl xanthines as described in this paper, constitutes a new series of selective adenosine ligands displaying bronchospasmolytic activity. The effect of substitution at third- and fourth-position of 8-phenyl xanthine has also been taken into consideration. The synthesized compounds showed varying binding affinities at different adenosine receptor subtypes (A1 , A2A , A2B , and A3 ) and also good in vivo bronchospasmolytic activity against histamine aerosol-induced asthma in guinea pigs. Most of the compounds showed maximum affinity toward the A2A receptor subtype. The monosubstituted 3-aminoalkoxyl 8-phenyl xanthine with a aminodiethyl moiety (compound 12e) was found to be most potent A2A adenosine receptor ligand (Ki = 0.036 ?M) followed by disubstituted 4-aminoalkoxyl-3-methoxy-8-phenyl xanthine (Ki = 0.050 ?M) (compound 10a).

[Bronchospasmolytic test]

Bronchodilation test using metered aerosols is a simple but extraordinary reliable method of respiratory functional diagnostics. It is highly sensitive (92%) and absolutely specific (100%) for demonstration of a pathologic elevated tonus of the bronchial musculature. The importance for the choice of therapy is limited. The main advantage concerns the diagnostic classification of the obstructive bronchopulmonary diseases.

[Bronchodilating inhalation anesthetics in bronchial asthma and status asthmaticus]

On the basis of a review of the literature, a survey is presented concerning the use of halogenated inhalational anaesthetics (halothane, enflurane, isoflurane) in anaesthesia of asthmatic patients and in intensive care units in the treatment of status asthmaticus refractory to maximal standard therapy. Particular emphasis is placed on the bronchospasmolytic, cardiovascular and organotoxic effect of the anaesthetics. It is concluded that halogenated inhalational anaesthetics are established as bronchospasmolytics, and that their use in bronchospastic disease should be individualized to the patient and his other specific disease process.

Cardiopulmonary effects of clenbuterol in the horse

Clenbuterol, a bronchospasmolytic agent (beta 2 agonist) was studied in terms of its hemodynamic and airflow response in eight, healthy horses. Four animals were instrumented to record intrapleural pressure and air flow, these were used to compute pulmonary resistance, peak flow rates, and tidal volumes. Four animals were instrumented to record pulmonary arterial pressure, carotid arterial pressure, cardiac output, and arterial gas tensions. After control values were recorded, clenbuterol (0.8 microgram/kg) was intravenously administered to each horse in each experiment group. Following clenbuterol administration, non-elastic resistance of the lung or pulmonary resistance significantly decreased, 33.6% reduction at 10 min post-clenbuterol. Pulmonary resistance remained lowered during the entire procedure and showed no tendency of returning toward control values by 3 h post-clenbuterol. Within 30 sec following clenbuterol injection carotid arterial pressure decreased (mean pressure decrease 28.2%). Accompanying the change in arterial pressure, the heart rate drastically increased, 99.0%. Both changes were transient and returned to control ranges within 2 min. Clenbuterol appears to be effective in reducing non-elastic resistance of the lung, however intravenous administration to an animal with pre-existing cardiovascular or cardiopulmonary disease should be avoided.

Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity

The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also been studied. The compounds displayed moderate to potent binding affinities toward various adenosine receptor subtypes when evaluated through radioligand binding studies. However, most of the compounds showed the maximum affinity for the A2A subtype, some with high selectivity versus all other subtypes. Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-position of the 8-phenylxanthine scaffold was identified as the most potent A2A adenosine receptor ligand with Ki=0.06μM. Similarly potent and highly A2A-selective are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs.