Since the elucidation of the structure of substance P (Arg - Pro - Lys - Pro - Gin - Gin - Phe - Phe - Gly - Leu -Met - NH2) by Chang, Leeman & Niall (1971), many SP-analogs have been described and have provided important information about the sequence-activity relationships of SP. These studies have revealed the importance of chain length and of Phe7, Leu10 and Met11 for SP smooth muscle activity (Bergmann et al. 1974, Rosell et al. 1977). Thus, the smooth muscle stimulating activity is confined to the hexa-peptide sequence at the C-terminal. The (IIe7)-SP analog showed little or no smooth muscle stimulating activity (Leban et al. 1979). Yamaguchi et al. (1979) synthesized (D-Phe7)-SP which was found to be a weak partial agonist on the guinea-pig ileum. Likewise, (D-Pro2)-SP and (D-Leu8, D-Phe9)-SP exerted some SP-antagonism. A series of newly designed SP-analogs has been tested for possible SP-antagonism. We have found that (D-Pro2, D-Phe7, D-Trp9)-SP is an inhibitor of SP both on isolated organs and in vivo.