2( S)-((3,5-Bis(trifluoromethyl)benzyl)-oxy)-3( S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742,694) is a selective morpholino tachykinin NK 1 receptor antagonist that inhibits the binding of 125I-substance P to the human tachykinin NK 1 receptor with a K d=37 pM. Increasing concentrations of L-742,694 added to cells 15 min prior to agonist progressively increase the apparent EC 50 of substance P for inducing the synthesis of inositol phosphate in Chinese hamster ovary (CHO) cells expressing human tachykinin NK 1 receptor and decrease the maximal level of stimulation observed. In contrast, addition of substance P and L-742,694 to the cells at the same time results in an increase in the EC 50 for substance P with no decrease in the maximal level of stimulation. The compound also decreases the apparent number of binding sites for 125I-substance P observed by Scatchard analysis. Analysis of the binding of [ 3H]L-742,694 to the tachykinin NK 1 receptor shows that it associates with the receptor with k a=3.98×10 8 M −1 min −1, and dissociates with k d=0.026 min −1 and t 1/2=27 min at 22°C. The slow rate of dissociation of L-742,694 from the tachykinin NK 1 receptor and the observation that altering the order of addition of antagonist and substance P attenuates the effect of the antagonist on the maximal activation suggest that L-742,694 is a competitive antagonist that can behave as a pseudoirreversible antagonist under some experimental conditions. L-742,694 has reduced affinity for tachykinin NK 1 receptors in which alanine has been substituted for Gln 165, His 197 or His 265 in transmembrane helices 4, 5 and 6, respectively. These three residues have previously been shown to be present in the binding site of tachykinin NK 1 receptor antagonists of several structural classes. In addition, L-742,694 inhibits binding of the quinuclidine antagonist (2 S,3 S)- cis-2-(diphenyl methyl)- N-[(2-iodophenyl)-methyl]-1-azabicyclo[2.2.2]octane 3-amine ([ 125I]L-703,606) with the same affinity as it inhibits binding of 125I-substance P. These data indicate that L-742,694 binds to the same site within the transmembrane domain of the receptor as previously described competitive antagonists. © 1997 Elsevier Science B.V.