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

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-lactonel 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-mu-g kg-1)-, NKA (1.1-mu-g kg-1)- and capsaicin (3.1-mu-g 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-mu-g kg-1)-, NKA (11-mu-g kg-1)- and capsaicin (100-mu-g 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. In agreement with the results of in vitro experiments, histamine-and acetylcholine-induced airway constriction, and histamine-induced airway edema, were not affected by FK224. These results suggest that FK224 is a selective NK receptor antagonist which inhibits airway constriction and airway edema induced not only by exogenous SP and NKA, but also by the endogenous neurotransmitter(s) released by neurogenic stimulation.