Novel triple neurokinin receptor antagonist CS-003 strongly inhibits neurokinin related responses.
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.
Tsuchida
Hiroshi
H
Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Tokyo, 134-8630, Japan.
Takahashi
Sakiko
S
Nosaka
Emi
E
Mukaiyama
Osamu
O
Yamashita
Makoto
M
Morimoto
Kiyoshi
K
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
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