新型选择性NK1受体拮抗剂SDZ NKT 343的比较性和一般药理学

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

作者信息

Walpole C S, Brown M C, James I F, Campbell E A, McIntyre P, Docherty R, Ko S, Hedley L, Ewan S, Buchheit K H, Urban L A

机构信息

Novartis Institute for Medical Sciences, London.

出版信息

Br J Pharmacol. 1998 May;124(1):83-92. doi: 10.1038/sj.bjp.0701806.

DOI:10.1038/sj.bjp.0701806

PMID:9630347

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565365/

Abstract

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 NK1 receptor antagonist was investigated. 2. SDZ NKT 343 inhibited [3H]-substance P binding to the human NK1 receptor in transfected Cos-7 cell membranes (IC50 = 0.62+/-0.11 nM). In comparison, in the same assay Ki 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, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50 = 451+/-139 nM). 3. SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]-substance P, suggesting a non-competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism 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 transfected Cos-7 cells (Ki of 0.52+/-0.04 microM and 3.4+/-1.2 microM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ 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 NK1 receptors expressed in Cos-7 cell membranes. 5. Contractions of the guinea-pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC50 = 1.60+/-0.94 nM, while the enantiomer (R,R)-SDZ NKT 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 888 were 2.90+/-07 nM, 0.14+/-0.02 nM, 11.4+/-2.9 nM and 2.4+/-0.83 nM, respectively. 6. In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar9]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 highly selective NK1 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 NK1 receptor hyperfunction is involved.

摘要

对新型速激肽NK1受体拮抗剂SDZ NKT 343（2-硝基苯基-氨基甲酰基-（S）-脯氨酰基-（S）-3-（2-萘基）丙氨酰基-N-苄基-N-甲基酰胺）进行了体外和体内药理学研究。
SDZ NKT 343抑制[3H]-P物质与转染的Cos-7细胞膜中人NK1受体的结合（IC50 = 0.62±0.11 nM）。相比之下，在相同试验中，FK888、CP 99,994、SR 140,333和RPR 100,893的Ki值分别为2.13±0.04 nM、0.96±0.20 nM、0.15±0.06 nM和1.77±0.41 nM。SDZ NKT 343在前脑全细胞膜中对大鼠NK1受体的亲和力明显较低（IC50 = 451±139 nM）。
SDZ NKT 343导致[3H]-P物质的EC50增加以及结合位点数量（Bmax）减少，表明其与人NK1受体存在非竞争性相互作用。SDZ NKT 343还可降低P物质（SP）在人U373MG细胞中诱发的[Ca2+]i最大升高，并抑制[Sar9]SP磺酸盐诱导的豚鼠离体回肠最大收缩。SDZ NKT 343对U373MG细胞中SP效应的拮抗作用是可逆的。
SDZ NKT 343对转染的Cos-7细胞中的人NK2和NK3受体亲和力较弱（Ki分别为0.52±0.04 μM和3.4±1.2 μM）。SDZ NKT 343在包括缓激肽B2受体、组胺H1受体、阿片受体和肾上腺素受体在内的一系列结合试验中均无活性。SDZ NKT 343仅微弱抑制豚鼠背根神经节神经元中的电压激活Ca²⁺和Na⁺电流。SDZ NKT 343的对映体（R,R）-SDZ NKT 343在Cos-7细胞膜中表达的人NK1受体上的活性约低1000倍。
SDZ NKT 343以浓度依赖性方式抑制[Sar9]SP磺酸盐引起的豚鼠回肠收缩，IC50 = 1.60±0.94 nM，而对映体（R,R）-SDZ NKT 343的活性低100倍（IC50 = 162±26 nM）。相比之下，在相同试验中，其他NK1受体拮抗剂CP 99,994、SR 140,333、RPR 100,893和FK 888的IC50值分别为2.90±0.07 nM、0.14±0.02 nM、11.4±2.9 nM和2.4±0.83 nM。
在麻醉的豚鼠中，静脉注射SDZ NKT 343可拮抗[Sar9]SP磺酸盐诱发的支气管收缩（静脉注射0.4 mg kg⁻¹时降低70%）。基础气道阻力、平均动脉血压和心率未受影响。
总之，SDZ NKT 343是一种高度选择性的NK1受体拮抗剂，对人和豚鼠受体具有高效力。SDZ NKT 343可能作为一种潜在的新型治疗药物用于涉及NK1受体功能亢进的人类疾病。