Characterization of the binding and activity of a high affinity, pseudoirreversible morpholino tachykinin NK1 receptor antagonist

European Journal of Pharmacology
M A CascieriC D Strader

Abstract

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 NK1 receptor antagonist that inhibits the binding of 125I-substance P to the human tachykinin NK1 receptor with a Kd = 37 pM. Increasing concentrations of L-742,694 added to cells 15 min prior to agonist progressively increase the apparent EC50 of substance P for inducing the synthesis of inositol phosphate in Chinese hamster ovary (CHO) cells expressing human tachykinin NK1 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 EC50 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 NK1 receptor shows that it associates with the receptor with k(a) = 3.98 x 10(8) M(-1) min(-1), and dissociates with k(d) = 0.026 min(-1) and t1/2 = 27 min at 22 degrees C. The slow rate of dissociation of L-742,694 from the tachykinin NK1 receptor and the observation that altering the o...Continue Reading

References

Jul 7, 1992·European Journal of Pharmacology·A NagahisaH J Hess
Jan 25, 1991·Science·R M SniderR W Spencer
Sep 1, 1980·Analytical Biochemistry·P J Munson, D Rodbard
Jul 19, 1994·Proceedings of the National Academy of Sciences of the United States of America·H T SchambyeT W Schwartz
Jan 1, 1994·Journal of Receptor Research·K E MazinaT M Fong
Jul 9, 1993·Journal of Medicinal Chemistry·A M MacLeodR Baker
Aug 1, 1995·Journal of Pharmacological and Toxicological Methods·M A CascieriC D Strader
Jul 19, 1996·Journal of Medicinal Chemistry·T LadduwahettyR J Hargreaves

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