title: 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.
authors.affiliation: Department of Chemistry, University of Patras, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Antoniou
authors.forename: C
authors.initials: C
authors.lastname: Poulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008715:Methionine / Q000737:chemistry*; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000737:chemistry*
chemical_list: D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D013373:Substance P; C032682:substance P (4-11); D008715:Methionine