title: Novel triple neurokinin receptor antagonist CS-003 strongly inhibits neurokinin related responses.
abstract: Neurokinins are known to induce neurogenic inflammation related to respiratory diseases, though there is little information on triple neurokinin receptor antagonists. The pharmacological properties of the novel triple neurokinin 1, 2 and 3 receptor antagonist [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] (CS-003) were evaluated in this study. The binding affinities of CS-003 were evaluated with human and guinea pig neurokinin receptors. As well, the in vivo antagonism of CS-003 against exogenous neurokinins and effects on capsaicin-induced and citric acid-induced responses were investigated in guinea pigs. CS-003 exhibited high affinities for human neurokinin 1, neurokinin 2 and neurokinin 3 receptors with Ki values (mean+/-S.E.M.) of 2.3+/-0.52, 0.54+/-0.11 and 0.74+/-0.17 nM, respectively, and for the guinea pig receptors with Ki values of 5.2+/-1.4, 0.47+/-0.075 and 0.71+/-0.27 nM, respectively. Competitive antagonism was indicated in a Schild analysis of substance P-, neurokinin A- and neurokinin B-induced inositol phosphate formation with pA2 values of 8.7, 9.4 and 9.5, respectively. CS-003 inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID50 values of 0.13, 0.040 and 0.063 mg/kg (i.v.), respectively. CS-003 also inhibited capsaicin-induced bronchoconstriction (ID50: 0.27 mg/kg, i.v.), which is caused by endogenous neurokinins. CS-003 significantly inhibited citric acid-induced coughs and the effect was greater than those of other selective neurokinin receptor antagonists. CS-003 is a potent antagonist of triple neurokinin receptors and may achieve the best therapeutic efficacy on respiratory diseases associated with neurokinins compared to selective neurokinin receptor antagonists.
authors: Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Tokyo, 134-8630, Japan.
authors: Hiroshi
authors: H
authors: Tsuchida
authors: Sakiko
authors: S
authors: Takahashi
authors: Emi
authors: E
authors: Nosaka
authors: Osamu
authors: O
authors: Mukaiyama
authors: Makoto
authors: M
authors: Yamashita
authors: Kiyoshi
authors: K
authors: Morimoto
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects; D019556:COS Cells; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002522:Chlorocebus aethiops; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000517:prevention & control; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology*; D015288:Neurokinin A / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015287:Neurokinin B / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply / Q000187:drug effects
chemical_list: C530698:1-(2-(2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl)ethyl)spiro(benzo(c)thiophene-1(3H),4'-piperidine)-2-oxide; D003499:Cyclic S-Oxides; D004151:Dipeptides; D007211:Indoles; D007295:Inositol Phosphates; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C078949:FK 888; D019343:Citric Acid; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B; D002211:Capsaicin