title: Studies on neurokinin antagonists. 1. The design of novel tripeptides possessing the glutaminyl-D-tryptophylphenylalanine sequence as substance P antagonists.
abstract: To discover a novel and low molecular weight substance P (SP) antagonist we postulated that the essential binding domain of peptide ligands was only a small portion in the whole structure. On the basis of this assumption, we selected the known octapeptide SP antagonist D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Phe-NH2 (1) as a lead and synthesized its fragment tripeptides which were evaluated for their activity to block 3H-SP binding on guinea pig lung membranes. The protected tripeptide N alpha-[N alpha-[N alpha-(tert-butyloxycarbonyl)-L-glutaminyl]-N1-formyl-D-tryptophyl]- L-phenylalanine benzyl ester [Boc-Gln-D-Trp(CHO)-Phe-OBzl (4a)], corresponding to the Gln-D-Trp-Phe part of 1, exhibited 7-fold potent inhibitory activity in comparison with 1. Studies on structure-activity relationships revealed that the D-tryptophan, L-phenylalanine, and benzyl ester were quite important to maintain the high binding affinity. It was also indicated that 4a antagonized the SP-induced contraction of isolated guinea pig trachea strips (IC50 = 4.7 x 10(-6) M).
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Hagiwara
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: H
authors.initials: H
authors.lastname: Morimoto
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D009842:Oligopeptides; D010446:Peptide Fragments; C074912:N(alpha)-(N(alpha)-(N(alpha)-(tert-butyloxycarbonyl)glutaminyl)-N(1)-formyl-tryptophyl)phenylalanine benzyl ester; D013373:Substance P