Analogs of substance P. Peptides containing D-amino acid residues in various positions of substance P and displaying agonist or receptor selective antagonist effects

Abstract

Agonist and antagonist analogues of substance P were synthesized by replacing at least two of the amino acid residues with D-Trp, D-Phe, D-Val, or D-Pro residues. The syntheses of these compounds were achieved by solid-phase methodology using the hydroxymethyl resin. The analogues were tested for agonist and antagonist activity on guinea pig ileum and rat spinal cord preparations. Two types of antagonists were obtained. The first type of compounds, e.g., [N alpha-Z-Arg1,N epsilon-Z-Lys3,D-Trp7,8,D-Met11]-SP-OMe (1), antagonized SP and SP(6-11)-hexapeptide on the ileum but only SP(6-11)-hexapeptide on the spinal cord. The second type of antagonists, e.g., [N alpha-Z-Arg1,N epsilon-Z-Lys3,D-Pro9,10]-SP-OMe (17), were inactive on the ileum but were potent antagonists of the hexapeptide on the spinal cord. Two of the antagonists, [N alpha-Z-Arg1,N epsilon-Z-Lys3,D-Trp7,8,D-Met11]-SP (3) and [D-Trp7,8,9]-SP (43), were also tested in vivo. Both of these depressed hypotensive responses to SP and SP(6-11)-hexapeptide in rabbits.

Substance P: Structure, Function, and Therapeutics

“…An exploratory study on tachykinin antagonists was initiated by Folkers'group [197], who first reported the synthesis of SP antagonists [198], followed by Escher [69] and others [199]. These groups have developed an approach to modify the structure of SP and the neurokinins by systematic introduction of D-amino acid residues (particularly D-Trp and D-Phe).…”