Vol. 280, Issue 2, 774-785, 1997

LY303870, a Centrally Active Neurokinin-1 Antagonist with a Long Duration of Action

S. Iyengar, P. A. Hipskind, D. R. Gehlert, D. Schober, K. L. Lobb, J. A. Nixon, D. R. Helton, M. J. Kallman, S. Boucher, R. Couture, D. L. Li and R. M. A. Simmons

CNS Research (S.I., P.A.H., D.R.G., D.S., K.L.L., J.A.N., D.L.L., R.M.A.S.) and Toxicology Research (D.R.H., M.J.K.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, and Department of Physiology, University de Montreal, Montreal, Quebec, Canada (S.B., R.C.)

The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with ¹²⁵I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg⁶,Sar⁹,Met(O₂)¹¹]substance P_6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar⁹,Met(O₂)¹¹]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with ¹²⁵I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses of 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity.