Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK 1 receptor antagonist

The in vitro and in vivo pharmacology of SDZ NKT 343 (2‐nitrophenyl‐carbamoyl‐( S )‐prolyl‐( S )‐3‐(2‐naphthyl)alanyl‐N‐benzyl‐N‐methylamide), a novel tachykinin NK 1 receptor antagonist was investigated. SDZ NKT 343 inhibited [ 3 H]‐substance P binding to the human NK 1 receptor in transfected Cos‐7 cell membranes (IC 50 =0.62±0.11 n M ). 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 n M , 0.96±0.20 n M , 0.15±0.06 n M and 1.77±0.41 n M , respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK 1 receptors in whole forebrain membranes (IC 50 =451±139 n M ). SDZ NKT 343 caused an increase in EC 50 as well as reduction in the number of binding sites (B max ) determined for [ 3 H]‐substance P, suggesting a non‐competitive interaction at the human NK 1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca 2+ ] i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar 9 ]SP sulphone‐induced contraction of the guinea‐pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible. SDZ NKT 343 showed weak affinity to human NK 2 and NK 3 receptors in transfected Cos‐7 cells ( K i of 0.52±0.04 μ M and 3.4±1.2 μ M , respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B 2 receptor the histamine H 1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage‐activated Ca 2+ and Na + currents in guinea‐pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, ( R , R )‐SDZ NKT 343 was about 1000 times less active at human NK 1 receptors expressed in Cos‐7 cell membranes. Contractions of the guinea‐pig ileum by [Sar 9 ]SP sulphone were inhibited by SDZ NKT 343 in a concentration‐dependent manner, with an IC 50 =1.60±0.94 n M , while the enantiomer ( R , R )‐SDZ NKT 343 was 100 times less active (IC 50 =162±26 n M ). In comparison, in the same assay IC 50 values for other NK 1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 n M , 0.14±0.02 n M , 11.4±2.9 n M and 2.4±0.83 n M , respectively. In anaesthetized 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. In conclusion, SDZ NKT 343 is a highly selective NK 1 receptor antagonist with high potency at the human and guinea‐pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK 1 receptor hyperfunction is involved.