title: A new nonpeptide tachykinin NK1 receptor antagonist isolated from the plants of Compositae.
abstract: 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 Ki 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.
authors.affiliation: Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., Hyogo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Ko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Furukawa
authors.forename: Yukari
authors.initials: Y
authors.lastname: Konishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogino
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Higashiura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yago
authors.forename: Kaoru
authors.initials: K
authors.lastname: Okamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Otsuka
mesh_terms: D000475:Alkenes / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D019659:Asteraceae / Q000737:chemistry*; D001372:Aza Compounds / Q000302:isolation & purification / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D020843:Chamomile / Q000737:chemistry; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010936:Plant Extracts / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000378:metabolism*
chemical_list: D000475:Alkenes; D001372:Aza Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010936:Plant Extracts; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C460561:tetracoumaroyl spermine; D013373:Substance P