IMPROVED DISCRIMINATORY PROPERTIES BETWEEN HUMAN AND MURINE TACHYKININ NK1 RECEPTORS OF MEN-10930 - A NEW POTENT AND COMPETITIVE ANTAGONIST

MEN 10930 (N ino-cyclohexane-1-carbonyl}L-3-(2-naphthyl)alanine N-(ben zyl) N methyl amide) interacts with high affinity with NK1 tachykinin receptor expressed in human IM9 (K-i=1.0 +/- 0.17 nM) and U373MG (K-i= 2.8+/-0.5 nM) cells and guinea pig lung membranes (K-i=5.9+/-0.8 nM). MEN 10930 shows no affinity for NK1 sites present in rat urinary bladd er membranes up to 10 mu M: resulting in more than 10000-fold selectiv ity for the human NK1 receptor. In Scatchard plots performed in IM9 ce lls, MEN 10930 affects the substance P affinity, without changing the B-max, suggesting a competitive interaction. It shows negligible affin ity for calcium channels (K-i=1.6+/-0.6 mu M), NK2 receptor (K-i=1.5+/ -0.5 mu M) End for NK3 receptor (K-i > 10 mu M). Furthermore, MEN 1093 0 inhibits in a competitive manner the SP methyl ester-induced contrac tions in guinea pig ileum (pA(2)=8.7+/-0.08). In conclusion, MEN 10930 is a potent, selective, competitive antagonist of human, but not muri ne, NK, receptor.