Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist

摘要: 1. The in vitro and vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide), a novel tachykinin NK1 receptor antagonist was investigated. 2. inhibited [3H]-substance P binding to the human transfected Cos-7 cell membranes (IC50 = 0.62+/-0.11 nM). In comparison, same assay Ki values for FK888, CP 99,994, SR 140,333 RPR 100,893 were 2.13+/-0.04 nM, 0.96+/-0.20 0.15+/-0.06 nM 1.77+/-0.41 respectively. showed markedly lower affinity at rat receptors whole forebrain 451+/-139 3. caused an increase EC50 as well reduction number sites (Bmax) determined P, suggesting non-competitive interaction receptor. also maximum elevation [Ca2+]i evoked by substance (SP) U373MG cells depressed [Sar9]SP sulphone-induced contraction guinea-pig isolated ileum. antagonism SP effects on reversible. 4. weak NK2 NK3 (Ki 0.52+/-0.04 microM 3.4+/-1.2 microM, respectively). inactive broad array assays including bradykinin B2 histamine H1 receptor, opiate adrenoceptors. only weakly voltage-activated Ca2+ Na+ currents dorsal root ganglion neurones. enantiomer 343, (R,R)-SDZ about 1000 times less active expressed membranes. 5. Contractions ileum sulphone concentration-dependent manner, with IC50 1.60+/-0.94 while 100 162+/-26 other antagonists 140,333, FK 888 2.90+/-07 0.14+/-0.02 11.4+/-2.9 2.4+/-0.83 6. anaesthetized guinea-pigs i.v. administered antagonized sulphone-evoked bronchoconstriction (70% 0.4 mg kg(-1), i.v.). Basal airway resistance, mean arterial blood pressure heart rate not affected. 7. conclusion, is highly selective high potency receptors. may be used potential therapeutic agent diseases where hyperfunction involved.