title: Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerve stimulation in guinea pigs.
abstract: FK224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2- penthylphenyl)-propionyl]-L-threonyl]tyrosyl]-L-leucynyl]-D- phenylalanyl]-L-allo-threonyl]-L-asparaginyl]-L-serine-nu-lactone) is a novel neurokinin (NK) antagonist that exhibits selectivity for NK1 and NK2 receptors. The effects of FK224 on airway constriction and airway edema induced by NKs and nerve stimulation have been investigated in guinea pigs. FK224 inhibited the contraction of isolated guinea pig trachea induced by substance P (SP, 10(-8) M), NKA (10(-9) M) and NKB (10(-8) M) in a concentration-dependent manner, and the IC50 values were 2.6 x 10(-6), 1.3 x 10(-6) and 2.3 x 10(-7) M, respectively. Tracheal contraction induced by histamine and acetylcholine was not affected by FK224, suggesting a specific effect on NK-mediated responses. FK224 also inhibited the atropine-resistant contraction of isolated guinea pig bronchi induced by electrical field stimulation with an IC50 value of 3.5 x 10(-6) M. In in vivo experiments, FK224 given i.v. inhibited SP (13.5 micrograms kg-1)-, NKA (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction in guinea pigs with ED50 values of 0.39 mg kg-1, 0.36 mg kg-1 and 1.1 mg kg-1, respectively. FK224 also inhibited SP (1.3 micrograms kg-1)-, NKA (11 micrograms kg-1)- and capsaicin (100 micrograms kg-1)-induced airway edema with ED50 values of 0.14 mg kg-1, 0.29 mg kg-1 and 0.30 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: H
authors.initials: H
authors.lastname: Morimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: S
authors.initials: S
authors.lastname: Kiyotoh
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: T
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002211:Capsaicin / Q000009:adverse effects / Q000037:antagonists & inhibitors; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced* / Q000517:prevention & control*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013373:Substance P / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects*
chemical_list: D006633:Histamine Antagonists; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; C075570:FK 224; D013373:Substance P; D002211:Capsaicin