A New Nonpeptide Tachykinin NK₁ Receptor Antagonist Isolated from the Plants of Compositae

抄録

To find new tachykinin NK₁ 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 NK₁ receptor 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 1a, 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][Sar⁹, Met(O₂)¹¹]SP to human NK₁ receptors, were 21.9 nM and 3.3 nM, respectively. 1a is the first potent NK₁ 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 of Compositae. In 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.