Cellier E, Fayolle C, Hipskind P A, Iyengar S, Couture R
Department of Physiology, Faculty of Medicine, Universite de Montreal, Succursale Centre-Ville, Quebec, Canada.
Eur J Pharmacol. 1996 Dec 30;318(2-3):377-85. doi: 10.1016/s0014-2999(96)00808-4.
Three novel non-peptide tachykinin NK1 receptor antagonists were assessed on the transient fall in mean arterial blood pressure and the salivation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anaesthetized rat. LY303241 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- phenylpiperazin-1-yl)acetyl)amino]propane), LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(++ +piperidin-1 -yl)piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -cyclohexylpiperazin-1-yl)acetyl)amino]propane) (65 nmol-9 micromol/kg i.v.; 5 min earlier) inhibited both the vasodepressor and salivary responses to substance P in a dose-dependent manner. LY303241 and LY306740 were more potent in inhibiting the vascular response to substance P while LY303870 was more potent in inhibiting the salivary response. LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively. The antagonists act in a stereoselective and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of substance P. In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Only LY303241 attenuated the decreases in mean arterial pressure and heart rate evoked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The difference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascribed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.
在乌拉坦麻醉的大鼠中，评估了三种新型非肽类速激肽NK1受体拮抗剂对静脉注射P物质（0.65 nmol/kg）所致平均动脉血压短暂下降和唾液分泌的影响。LY303241（(R)-1-[N-(2-甲氧基苄基)乙酰氨基]-3-(1H-吲哚-3-基)-2-[N-(2-(4-苯基哌嗪-1-基)乙酰)氨基]丙烷）、LY303870（(R)-1-[N-(2-甲氧基苄基)乙酰氨基]-3-(1H-吲哚-3-基)-2-[N-(2-(4-(++ +哌啶-1-基)哌啶-1-基)乙酰)氨基]丙烷）和LY306740（(R)-1-[N-(2-甲氧基苄基)乙酰氨基]-3-(1H-吲哚-3-基)-2-[N-(2-(4-环己基哌嗪-1-基)乙酰)氨基]丙烷）（静脉注射65 nmol - 9 μmol/kg；提前5分钟）以剂量依赖性方式抑制了对P物质的血管降压和唾液反应。LY303241和LY306740在抑制对P物质的血管反应方面更有效，而LY303870在抑制唾液反应方面更有效。LY303870和LY306740没有直接作用，而LY303241分别使血压和心率在1分钟和10分钟内下降。这些拮抗剂以立体选择性和特异性方式起作用，因为LY303870（LY306155）和LY306740（LY307679）的对映体（S）不能阻断P物质的作用。此外，LY303241、LY303870和LY306740既不影响卡巴胆碱引起的低血压和唾液分泌，也不影响速激肽NK2受体激动剂[β-丙氨酸8]神经激肽A-(4-10)引起的平均动脉压和心率升高。只有LY303241减弱了速激肽NK3受体激动剂senktide引起的平均动脉压和心率下降。LY303870和LY306740似乎是最有意义的拮抗剂，因为它们以特异性和选择性方式作用于速激肽NK1受体。三种拮抗剂抑制P物质引起的低血压和唾液分泌的效价顺序差异可能归因于它们的药效学特征或不同信号转导机制或受体亚型的存在。
