Neurokinins are known to induce
neurogenic inflammation related to
respiratory diseases. The effects of
CS-003 ([1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo[c]
thiophene-1(3H),4'-
piperidine]-(2S)-
oxide hydrochloride]), a novel triple neurokinin receptor antagonist, on several respiratory disease models were evaluated in guinea pigs. As we have already shown that
CS-003 is intravenously effective, we first determined if
CS-003 was orally effective.
CS-003 dose-dependently inhibited
substance P-induced tracheal vascular hyperpermeability,
neurokinin A- and
neurokinin B-induced bronchoconstriction with ID(50) values of 3.6, 1.3 and 0.89 mg/kg (p.o.), respectively.
CS-003 (10 mg/kg, p.o.) inhibited the number of
coughs induced by
capsaicin aerosol (P<0.01) and the
antitussive effect was comparable to that of
codeine.
CS-003 (10 mg/kg, p.o.) also inhibited
airway hyperresponsiveness to
methacholine chloride in
ovalbumin-induced
asthma models (P<0.01), a milder one and a severer one. On the other hand,
montelukast (10 mg/kg, p.o.), a
leukotriene receptor antagonist, significantly inhibited the hyperresponsiveness only in the milder model (P<0.05). In an
ovalbumin-induced
rhinitis model,
oral administration of
CS-003 inhibited nasal blockade in a dose-dependent manner and the inhibitory effect was comparable to that of
dexamethasone (10 mg/kg, p.o.).
CS-003 (i.v.) also dose-dependently inhibited cigarette
smoke-induced bronchoconstriction, tracheal vascular hyperpermeability and mucus secretion. These data show that
CS-003, a potent orally active triple neurokinin receptor antagonist, may be useful for the treatment of
respiratory diseases associated with neurokinins, such as allergic
asthma,
allergic rhinitis,
chronic obstructive pulmonary disease and
cough.