HIGHLY POTENT SUBSTANCE-P ANTAGONISTS SUBSTITUTED WITH BETA-PHENYL-PROLINE OR BETA-BENZYL-PROLINE AT POSITION-10

In the guinea-pig ileum tissue, [Pro(9)]substance P, a tachykinin NK1 receptor selective agonist and septide, [pGlu(6),Pro(9)]substance P-(6 -11), do not interact with the same receptor as shown by the different inhibitory profiles of GR 72251 and [D-Pro(9),Pro(10),Trp(11)]substan ce P. Substitution at position 10 of the D-Pro(9)-Pro(10) moiety with bulky N-methylated amino acids increased the antagonist potency for th e tachykinin NK1 receptor without affecting that for the 'septide-sens itive receptor'. The incorporation of a trans-beta-L-substituted proli ne in position 10, for example a benzyl group (beta-benzyl-L-proline), afforded a potent antagonist active in the nanomolar range. For GR 82 334, this increase in potency was obtained at the expense of selectivi ty for tachykinin NK1 and 'septide-sensitive' receptors.