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

Abstract

Analogues of [Orn6]‐SP6–11 have been synthesized in which the Met11‐NH2 residue is replaced by the α,γ‐dimethyl, α,γ‐dibenzyl and α,γ‐di‐tert‐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‐tert‐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.