1-[3-(4-Benzhydryl-1-piperazinyl)propyl]-3-(1H-imidazol-1-ylmethyl)-1H-indole-6-carboxylic acid (GAS 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 A(2) (TXA(2)) 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), bur not pyrilamine, attenuated the contraction induced by leukotriene D-4 (LTD(4)) and platelet-activating factor in the lung parenchymal strips. In anesthetized guinea pigs, KY-234 (1-10 mg/kg p.o.) inhibited the LTD(4)- and histamine-induced bronchoconstriction. Ozagrel and terfenadine inhibited only the LTD(4)- 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 TXA(2) synthetase-inhibitory and H-1-blocking activity and protects against anaphylactic bronchospasm more effectively than a TXA(2) synthetase inhibitor or H-1-blocker alone.