Novel triple neurokinin receptor antagonist CS-003 inhibits respiratory disease models in guinea pigs

European Journal of Pharmacology
Hiroshi TsuchidaKiyoshi Morimoto

Abstract

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, ...Continue Reading

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Citations

Mar 2, 2011·The Journal of Reproduction and Development·Ken-ichi NoritakeHiroko Tsukamura
May 26, 2012·International Journal of Pediatric Otorhinolaryngology·Ozkaya EminDundaroz M Rusen
Oct 13, 2009·Pharmacology & Therapeutics·Julie Nasra, Maria G Belvisi
Mar 19, 2009·Pharmacology & Therapeutics·Tibor Z VeresArmin Braun
Dec 14, 2011·Expert Opinion on Therapeutic Patents·Maria Altamura
Jul 3, 2013·Pulmonary Pharmacology & Therapeutics·Stefano FogliMaria Cristina Breschi
Mar 29, 2014·Pharmacological Reviews·P V DicpinigaitisC P Page
Jun 6, 2020·Clinical Science·Mikael AdnerSven-Erik Dahlén
May 22, 2019·The Journal of Antibiotics·Ken-Ichi Kimura

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