Synthesis of an analogue of the substance P C-terminal hexapeptide with modification at the glutaminyl and methioninyl residues and increased activity in NK-2 receptor type: Structure-activity relationships

Abstract

Analogues of [Orn 6]-SP 6–11 have been synthesized in which the Met 11 residue is replaced by Hse(CH 3), Hse(Bzl), Nva(5-OCH 3), Nva(5-OBzl) and Abu. These analogues were tested in 3 in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types. The Hse(Bzl) analogue is 16.6-fold more potent than the parent hexapeptide at the NK-2 receptor and 2.4-fold more potent at the NK-3 receptor. The Nva(5-OCH 3) analogues howed weak antagonist activity in NK-2 and NK-3 receptor types, being a full agonist at NK-1. It is concluded from structure-activity correlations that the role of Met 11 side chain in substance P is associated with activity and/or efficacy, as appropriate modifications in the side chain may result either in agonists with increased activity compared to the parent hexapeptide or selective agonists or may induce antagonism.