PERIPHERAL EFFECTS OF 3 NOVEL NONPEPTIDE TACHYKININ NK1 RECEPTOR ANTAGONISTS IN THE ANESTHETIZED RAT

Three novel non-peptide tachykinin NK1 receptor antagonists were asses sed on the transient fall in mean arterial blood pressure and the sali vation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anae thetized rat. LY303241 ((R)-1-[N-(2- methoxybenzyl)acetylamino]-3-(1H- indol-3-yl)-2-[ (2-(4-(phenylpiperazin-1-yl)acetyl)amino]propane), LY3 03870 -1-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2- iperidin-1-yl )piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methox ybenzyl)acetylamino]-3-(1 )-2-[N-(2-(4-cyclohexylpipeazin-1-yl)acetyl) amino] propane (65 nmol-9 mu mol/kg i.v.; 5 min earlier) inhibited bot h the vasodepressor and salivary responses to substance P in a dose-de pendent manner. LY303241 and LY306740 were more potent in inhibiting t he 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 stereoselect ive and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of sub stance P. In addition, LY303241, LY303870 and LY306740 neither affecte d the hypotension and the salivation induced by carbachol nor the incr eases in mean arterial pressure and heart rate induced by the tachykin in NK2 receptor agonist [beta-Ala(8)] neurokinin A-(4-10). Only LY3032 41 attenuated the decreases in mean arterial pressure and heart rate e voked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY 306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The d ifference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascrib ed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.