A New Nonpeptide Tachykinin NK_1 Receptor Antagonist Isolated from the Plants of Compositae

概要

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To find new tachykinin NK_1 receptor antagonists from natural sources, we examined the tachykinin antagonist activity in the extracts of approximately 200 species of plants by the use of isolated guinea pig ileum. As a result, we discovered a novel and potent NK_1 recepton antagonist in the extract of dried flowers of Matricaria chamomilla L.(chamomile). The structure of the antagonist was established as N1, N5, N10, N14-tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]-1, 5, 10, 14-tetraazatetradecane(tetracoumaroyl spermine, 1a). The K_i values of la, estimated from the inhibitory action on the substance P(SP)-induced contraction of the guinea pig ileum and the inhibition of the binding of [^3H][Sar^9, Met(O_2)^<11>]SP to human NK_1 receptors, were 21.9nм and 3.3nм, respectively. 1a is the first potent NK_1 receptor antagonist from natural sources and it has a unique structure of a polyacylated spermine. 1a was concentrated in pollen of Matricaria chamomilla L.and was also found in the extracts of flowers of other four species or Compositae. ln addition, we found N1, N5, N10-tris[3-(4-hydroxyphenyl)-2-propenoyl]-1, 5, 10, 14-tetraazatetradecane(2)as a new compound in the extract of flowers of Matricaria chamomilla L., which did not exhibit any tachykinin antagonist activity. A number of related compounds were synthesized, and the structure-activity relationship was studied.
公益社団法人日本薬学会の論文
2002-01-01