Analogues of the C-terminal fragments of neurokinins with modifications at their C-terminal methionyl residue. Structure-activity studies.

Abstract

Analogues of SP4-11 have been synthesized in which the methionyl residue is replaced successively by the Glu(OCH2CH3), Glu(OBzl), Hse(CH3) and Glu(CONHCH3) residues, and analogues of NKA4-10 and NKB4-10 have been prepared in which the methionyl residue is replaced by the Hse(Bzl) and Hse(CH3) residues, respectively. The SP4-11 analogues were tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types. Substitution of the SCH3 group of the Met11 side chain by the groups COOCH2CH3 and COOBzl has little affect on the agonist activity in NK-1 preparations, while in NK-2 the corresponding analogues are more potent than the parent octapeptide; that substituted with COOBzl being 8.2 times more potent than SP4-11. In NK-3 preparations all analogues are weak agonists. The selectivity of all the analogues is reduced compared with the corresponding hexapeptide analogues. The SP4-11 analogues, along with those of NKA4-10 and NKB4-10, were tested for their binding ability in the three receptor subtypes above. The SP4-11 analogues show reduced affinity for NK-1 receptors, while the NKA4-10 and NKB4-10 analogues have almost the same affinities as NKA and NKB for NK-2 and NK-3 receptors, respectively. The effect of the lipophilicity of the Met11 side chain, especially when a phenyl group is present in the side chain, at the NK-2 receptor is discussed.