title: [Pharmacological profiles of a novel tachykinin NK-2 receptor antagonist, TAC-363].
abstract: We examined the pharmacological profiles of a novel tachykinin NK-2 receptor antagonist, Na-(tert-butylcarbamoyl)-L-glutaminyl-L-tryptophyl-alpha-azap++ + henylalanine 2-benzyloxyethylamide (TAC-363). In vitro studies showed that TAC-363 caused a rightward shift of the contraction response curve with a slight inhibition of maximal response for the neurokinin A (NKA)-induced contraction of the hamster trachea and parallel rightward shift of the curve for the substance P (SP)-induced contraction of the guinea-pig ileum. The pA2 values were 9.82 and 8.42 on the contraction by NKA and SP, respectively. The selectivity of TAC-363 to NK-2 receptor was 25 times higher than that to NK-1 receptor. The compound did not affect the histamine and acetylcholine-induced bronchoconstriction in guinea-pig ileum. Intravenous administration (0.1-1 mg/kg) of the compound inhibited dose-dependently both NKA- and capsaicin-induced bronchoconstriction in guinea-pigs. The inhibitory effect of the compound lasted up to 60 min on NKA-induced bronchoconstriction in guinea-pigs. These results suggest that TAC-363 is a potent and selective NK-2 receptor antagonist, which is effective in vitro and in vivo. It may be useful in the treatment of NKA-dependent pathology, especially bronchial asthma.
authors.affiliation: Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Higashide
authors.forename: Y
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Y
authors.initials: Y
authors.lastname: Arai
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
authors.forename: M
authors.initials: M
authors.lastname: Shibata
authors.forename: T
authors.initials: T
authors.lastname: Yamaura
mesh_terms: D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002211:Capsaicin / Q000037:antagonists & inhibitors; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*
chemical_list: D009842:Oligopeptides; D018039:Receptors, Tachykinin; C103891:TAC 363; D015288:Neurokinin A; D002211:Capsaicin