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Pharmacological profile of a high affinity dipeptide NK 1 receptor antagonist, FK888
Author(s) -
Fujii Takashi,
Murai Masako,
Morimoto Hiroshi,
Maeda Yasue,
Yamaoka Makiko,
Hagiwara Daijiro,
Miyake Hiroshi,
Ikari Norihiro,
Matsuo Masaaki
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14524.x
Subject(s) - guinea pig , antagonist , vas deferens , ileum , receptor , bioassay , pharmacology , receptor antagonist , in vivo , in vitro , biology , dipeptide , medicine , chemistry , endocrinology , biochemistry , amino acid , microbiology and biotechnology , genetics
1 In our search for compounds that inhibit the binding of [ 3 H]‐substance P (SP) to guinea‐pig lung membranes, the dipeptide SP antagonist, FK888, was developed by chemical modification of the parent compound, ( d ‐Pro 4 , d ‐Trp 7,9,10 , Phe 11 )SP 4– 11 . 2 In a [ 3 H]‐SP binding assay using guinea‐pig lung membranes and rat brain cortical synaptic membranes, FK888 displaced [ 3 H]‐SP binding with a K i value of 0.69 ± 0.13 n m and 0.45 ± 0.17 μ m , respectively, in a competitive manner. 3 FK888 inhibited the contraction of guinea‐pig isolated ileum induced by SP in the presence of atropine and indomethacin (a NK 1 receptor bioassay) with a pA 2 value of 9.29 (8.60–9.98). 4 FK888 inhibited contractions of rat vas deferens by NKA (a NK 2 receptor bioassay) and of rat portal vein by NKB (a NK 3 receptor bioassay) at concentrations at least 10,000 times greater than that required to inhibit contractions of guinea‐pig ileum. 5 FK888 also inhibited SP‐induced airway oedema in guinea‐pig after both intravenous and oral administration. 6 These data demonstrate that FK888 is a potent and selective NK 1 antagonist which is active both in vitro and in vivo .