Ws9326a, a Novel Tachykinin Antagonist Isolated

WS9326Abinds competitively to [3H]substance P (NK-1 receptor) binding sites on guinea-pig lung membranes(IC5O=3.6 x 10"6m), and acts as a tachykinin antagonist in various functional assays. WS9326A inhibited tracheal constrictions produced by exogenously added substance P and neurokinin A, with IC50 values of 9.7 x 10"6M and 3.5 x 10"6M, respectively. WS9326A inhibited neurokinin A-induced bronchoconstriction in a dose dependent manner when administered to guinea-pigs intravenously together with neurokinin A, and was also effective in preventing capsaicin-induced bronchoconstriction, which is known to be caused by release of endogenous tachykinins (substance P and neurokinin A). FK224 (tetrahydro-WS9326A; catalytic hydrogenation of WS9326Agave FK224) was more potent than WS9326Ain the [3H]substance P receptor binding assay using guinea-pig lung membrane (IC50= 1.0 x 10~7m).