Peripheral effects of three novel non-peptide tachykinin NK1 receptor antagonists in the anaesthetized rat

Abstract

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.