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.