title: Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist.
abstract: 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] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D001980:Bronchi / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014132:Trachea / Q000098:blood supply; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D007211:Indoles; D007295:Inositol Phosphates; D015850:Interleukin-6; D009842:Oligopeptides; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D014665:Vasodilator Agents; D013373:Substance P