Design and Synthesis of Antagonists of Substance P.

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Abstract
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 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-Nal5, 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 10-5M 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.

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