PHARMACOLOGICAL CHARACTERIZATION OF LY303870 - A NOVEL, POTENT AND SELECTIVE NONPEPTIDE SUBSTANCE-P (NEUROKININ-1) RECEPTOR ANTAGONIST

LY303870 iperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-l (NK-1) receptor antagonis t. LY303870 bound selectively and with high affinity to human peripher al (K-i = 0.15 nM) and central (K-i = 0.10 nM) NK-1 receptors. LY30387 0 inhibited [I-125]substance P (SP) binding to guinea pig brain homoge nates with similar affinity; however, it had approximately 50-fold les ser affinity for rat NK-1 sites. The less active enantiomer, LY306155 peridin-1-yl)piperidin-1-yl)acetyl)amino]propane}, was 1,000- to 15,00 0-fold less potent in all the species examined. LY303870 antagonized i n vitro NK-1 receptor effects as demonstrated by blockade of SP-stimul ated phosphoinositide turnover in UC-11 MG human astrocytoma cells (K- i = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytom a cells (K-i = 5 nM). In addition, LY303870 inhibited SP-induced rabbi t vena cava contractions (pA(2) = 9.4) with high (50,000-fold) selecti vity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 i nhibited [Sar(9),Met(O-2)(11)]-SP induced guinea pig bronchoconstricti on (ED(50) = 75 mu g/kg i.v.) and pulmonary microvascular leakage in t he bronchi (ED(50) = 12.8 mu g/kg i.v.) and trachea (ED(50) = 18.5 mu g/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 recepto r antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.