Design and synthesis of antagonists of substance P.
Synthesis and bioassay of about 65 analogs of substance P (SP) over five years yielded the antagonist [D-Arg1,D-Trp7,9,Leu11]-SP, which was named Spantide, and which was used by many investigators as a "tool". Spantide served as a reference antagonist for the design of 47 new peptides toward the goal of more potent inhibitors. Designs emphasized analogs with D-Trp7, D-Trp9, D-Trp10, D-pClPhe10, Nle11, Leu11, Ile11 and Met11, etc. Twenty-one/47 antagonists were superior in potency to that of Spantide, the best was [D-Arg1,D-Na1(5), D-Trp7,9,Nle11]-SP which required a 255-fold increase in SP concentration to give 50% of the maximum response at a concentration of 10(-5)M of the antagonist; this potency is ca. 5 times that of Spantide. For certain, but not all pairs of undecapeptides and truncated analogs, the undecapeptides may be significantly more potent than the truncated counterparts.
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007202:Indicators and Reagents; D009842:Oligopeptides / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D007202:Indicators and Reagents; D009842:Oligopeptides; D013373:Substance P