Effects of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-3- (1H-imidazol-1-ylmethyl)-1H-indole-6-carboxylic acid with thromboxane A2 synthetase inhibitory and H1-blocking activities on anaphylactic bronchospasm.Arzneimittelforschung 1996; 46(11):1067-71A
1-[3-(4-Benzhydryl-1-piperazinyl)propyl]-3-(1H-imidazol-1-ylmethyl )- 1H-indole-6-carboxylic acid (CAS 172544-75-1, KY-234) was characterized pharmacologically. KY-234 (10(-9)-10(-6) mol/l) and ozagrel (10(-8)-10(-5) mol/l) inhibited the production of thromboxane A2 (TXA2) in rabbit platelets. KY-234 and pyrilamine at concentrations of 10(-9)-10(-6) mol/l relaxed the isolated guinea pig trachea contracted with histamine, while neither drug attenuated the heart rate increased by histamine. Cimetidine antagonized histamine in the right atrium but not in the trachea. KY-234 (10(-8)-10(-5) mol/l) and ozagrel (10(-7)-10(-4) mol/l), but not pyrilamine, attenuated the contraction induced by leukotriene D4 (LTD4) and platelet-activating factor in the lung parenchymal strips. In anesthetized guinea pigs, KY-234 (1-10 mg/kg p.o.) inhibited the LTD4- and histamine-induced bronchoconstriction. Ozagrel and terfenadine inhibited only the LTD4- and histamine-induced constrictions. KY-234 (3-30 mg/kg p.o.) inhibited the anaphylactic bronchoconstriction continuously for 15 min after antigen-challenge. Terfenadine (3-30 mg/kg p.o.) inhibited the constriction more strongly within the first 5 min (fast phase) than it did within 5 to 15 min (slow phase) after the challenge. Ozagrel (100 mg/kg p.o.) slightly attenuated only the constriction during the slow phase. These findings demonstrated that KY-234 has a selective TXA2 synthetase-inhibitory and H1-blocking activity and protects against anaphylactic bronchospasm more effectively than a TXA2 synthetase inhibitor or H1-blocker alone.