Improved discriminatory properties between human and murine tachykinin NK1 receptors of MEN 10930: a new potent and competitive antagonist.
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 antagonist of human, but not murine, NK1 receptor.
Astolfi
M
M
Pharmacology Department Menarini Ricerche, Pomezia Rome, Italy.
Patacchini
R
R
Maggi
M
M
Manzini
S
S
D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008168:Lung; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth; D051381:Rats; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder
D007211:Indoles; C108844:MEN 10930; D018039:Receptors, Tachykinin; D000409:Alanine