Characterization of the interaction of N-acyl-L-tryptophan benzyl ester neurokinin antagonists with the human neurokinin-1 receptor.

摘要: We have recently shown that a series of N-acyl-L-tryptophan benzyl esters are potent substance P antagonists (Macleod, A. M., Merchant, K. J., Cascieri, M. A., Sadowski, S., Ber, E., Swain, C. and Baker, R. (1993) J. Med Chem. 14, 2044-2045). now report the detailed characterization interaction N-acetyl-L-tryptophan-3,5-bistrifluoromethyl ester (L-732,138) with human neurokinin-1 (NK-1) receptor. L-732,138 inhibits binding 125I-substance to cloned NK1 receptor expressed in Chinese hamster ovary cells an IC50 2.3 +/- 0.7 nM. In contrast, it has 200-fold lower affinity for rat NK-1 > 1000-fold NK-2 NK-3 receptors. acts as competitive antagonist P, by functional Schild analysis inhibition P-induced inositol phosphate synthesis, kinetic dissociation rate, thermodynamic equilibrium also competitively quinuclidine amine antagonist, [125I]L-703,606, The compound 230- 10-fold reduced mutant receptors which histidine 265 or 197, respectively, replaced alanine. previously these residues play key roles These results suggest tryptophan bind similar sites on