Highly potent substance P antagonists substituted with beta-phenyl- or beta-benzyl-proline at position 10

In the guinea-pig ileum tissue, [Pro9]substance P, a tachykinin NK1 receptor selective agonist and septide, [pGlu6,Pro9]-substance P-(6-11), do not interact with the same receptor as shown by the different inhibitory profiles of GR 72251 and [D-Pro9,Pro10,Trp11]substance P. Substitution at position 10 of the D-Pro9-Pro10 moiety with bulky N-methylated amino acids increased the antagonist potency for the tachykinin NK1 receptor without affecting that for the 'septide-sensitive receptor'. The incorporation of a trans-beta-L-substituted proline in position 10, for example a benzyl group (beta-benzyl-L-proline), afforded a potent antagonist active in the nanomolar range. For GR 82334, this increase in potency was obtained at the expense of selectivity for tachykinin NK1 and 'septide-sensitive' receptors.