Synthesis of potent antagonists of substance P by modifying the methionyl and glutaminyl residues of its C‐terminal hexapeptide and without using d‐amino acids

Analogues of [Orn 6 ]-SP 6 -11 have been synthesized in which the Met 1 1-NH 2 residue is replaced by the α,γ-dimethyl, α,γ-dibenzyl and α,γ-di-t-butyl esters of glutamic acid. These analogues were tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types for agonist and antagonist activity. The dimethyl analogue is a selective full agonist in the NK-1 receptor type and a weak antagonist in the other two receptor types, while the dibenzyl and the di-t-butyl analogues are potent antagonists in the NK-1 receptor type and weak antagonists in the other two receptor types. It is concluded that appropriate modification at the α-carboxamide and the side chain of the methionine residue of substance P may induce antagonism without using D-amino acids