IN-VITRO AND IN-VIVO CHARACTERIZATION OF MDL-105,212A, A NONPEPTIDE NK-1 NK-2 TACHYKININ RECEPTOR ANTAGONIST/

We have identified and characterized a novel, potent, nonselective tac hykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4-dichloroph enyl)-1 din-3-yl]-ethyl]-4-phenylpiperidine-4-carboxamide, hydrochlori de]. The compound binds with low nanomolar affinity and species specif icity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 r eceptors. In vitro functional assays are consistent with potent compet itive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [H- 3]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell l ines with pA(2) values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examine d in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway pl asma protein extravasation (ED(50) = 0.20 mg/kg, i.v.), NKA-induced re spiratory collapse (ED(50) = 5 mg/kg, i.v.) and inhibited capsaicin-in duced increases in pulmonary insufflation pressure (ED(50) = 0.5 mg/kg , i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and p lasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED(50) = 5 mg/kg) or oral (ED(50) = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity a nd its ability to inhibit SP and NKA mediated respiratory effects in v ivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.