Comparative evaluation of the relaxant effects of MDL‐257, its metabolits, and some related compounds on guinea pig tracheal cylindrical segments

Publisher Website
Google Scholar
Abstract
The smooth muscle relaxant activities of MDL‐257 [8‐methyl‐6‐piperidino‐s‐triazolo (4,3‐b)pyridazine], a new, nonsympathomimetic bronchodilator, its metabolites (in man and rats), and some related compounds were compared to that of aminophylline in guinea pig tracheal cylindrical segments. The IC50 of MDL‐257 against KCl‐, histamine‐, acetylcholine, and 5‐hydroxytryptamine‐induced contractions were 5.2 × 10−5, 5.3 × 10−5, 9.1 × 10−5, and 1.4 × 10−5M, respectively. The relaxant activity of aminophylline was equal to that of MDL‐257 against all of the spasmogens studied. Dihydroxy substitution on the piperidine ring of MDL‐257 reduced its relaxant activity against KCl, histamine, and 5‐hydroxytryptamine 25‐‐43‐fold and its activity against acetylcholine was almost abolished. The monohydroxy and the amino alcohol metabolites of MDL‐257 were two to 20 times less potent than the parent compound and their activities against acetylcholine‐induced contractions were minimal. The acidic metabolites of MDL‐257 exhibited very weak activity against all of the spasmogens tested.