COMPARATIVE, GENERAL PHARMACOLOGY OF SDZ NKT 343, A NOVEL, SELECTIVE NK1 RECEPTOR ANTAGONIST

1 The in vitro and in vivo pharmacology of SDZ NKT 343 l-(S)-3-(2-naph thyl)alanyl-N-benzyl-N-methylamide) a novel tachykinin NK1 receptor an tagonist was investigated. 2 SDZ NKT 343 inhibited [H-3]-substance P b inding to the human NK1 receptor in transfected Cos-7 cell membranes ( IC50 = 0.62 +/- 0.11 nM). In comparison, in the same assay K-i values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13 +/- 0.04 nM , 0.96 +/- 0.20 nM, 0.15 +/- 0.06 nM and 1.77 +/- 0.41 nM, respectivel y. SBZ NKT 343 showed a markedly lower affinity at rat NK1 receptors i n whole forebrain membranes (IC50 = 451 +/- 139 nM). 3 SDZ NKT 343 cau sed an increase in EC50 as well as reduction in the number of binding sites (B-max) determined for [H-3]-substance P, suggesting a non-compe titive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [C2+](i) evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar(9)]SP sulph one-induced contraction of the guinea-pig isolated ileum. The antagoni sm of SP effects on U373MG cells by SDZ NKT 343 was reversible. 4 SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfe cted Cos-7 cells (K-i of 0.52 +/- 0.04 mu M and 3.4 +/- 1.2 mu M, resp ectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B-2 receptor the histamine H-1 receptor, opi ate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ and Na+ currents in guinea-pig dorsal root gan glion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was a bout 1000 times less active at human NK1 receptors expressed in Cos-7 cell membranes. 5 Contractions of the guinea-pig ileum by [Sar(9)]SP s ulphone were inhibited by SDZ NKT 343 in a concentration-dependent man ner, with an IC50 = 1.60 +/- 0.94 nM, while the enantiomer (R,R)-SDZ N KT 343 was 100 times less active (IC50 = 162 +/- 26 nM). In comparison , in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 858 were 2.90 +/- 07 nM, 0.14 /- 0.02 nM, 11.4 +/- 2.9 nM and 2.4 +/- 0.83 nM, respectively. 6 In an aesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar (9)]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg (-1), i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected. 7 In conclusion, SDZ NKT 343 is a highl y selective NK1 receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel th erapeutic agent inhuman diseases where NK1 receptor hyperfunction is i nvolved.