Improved discriminatory properties between human and murine tachykinin NK1 receptors of MEN 10930: a new potent and competitive antagonist.

摘要

MEN 10930 (N alpha(N-[(1H)indol-3-yl-carbonyl]1-amino- cyclohexane-1-carbonyl)L-3-(2-naphthyl)alanine N-(benzyl) N methyl amide) interacts with high affinity with NK1 tachykinin receptor expressed in human IM9 (Ki = 1.0 +/- 0.17 nM) and U373MG (Ki = 2.8 +/- 0.5 nM) cells and guinea pig lung membranes (Ki = 5.9 +/- 0.8 nM). MEN 10930 shows no affinity for NK1 sites present in rat urinary bladder membranes up to 10 microM, resulting in more than 10,000-fold selectivity for the human NK1 receptor. In Scatchard plots performed in IM9 cells, MEN 10930 affects the substance P affinity, without changing the Bmax, suggesting a competitive interaction. It shows negligible affinity for calcium channels (Ki = 1.6 +/- 0.6 microM), NK2 receptor (Ki = 1.5 +/- 0.5 microM) and for NK3 receptor (Ki > 10 microM). Furthermore, MEN 10930 inhibits in a competitive manner the SP methyl ester-induced contractions in guinea pig ileum (pA2 = 8.7 +/- 0.08). In conclusion, MEN 10930 is a potent, selective, competitive antagonistof human, but not murine, NK1 receptor.