We have identified and characterized a novel, potent, nonselective
tachykinin receptor antagonist,
MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and
NK-2 receptors as well as to guinea pig
NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of
substance P-(SP) or
neurokinin A-(NKA) induced [3H]-
inositol phosphate accumulation in NK-1 or
NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and
capsaicin-mediated respiratory effects was examined in guinea pigs in vivo.
MDL 105,212A attenuated SP-induced airway
plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited
capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to
capsaicin aerosol exposure with
dyspnea,
coughs and gasps (significant respiratory events) and
plasma protein extravasation.
MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 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 and its ability to inhibit SP and NKA mediated respiratory effects in vivo 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.