title: Design and synthesis of dimeric analogs of neurokinin A and B: effect of dimerization of COOH-terminal heptapeptides on receptor selection.
abstract: Dimeric analogs of neurokinin A and neurokinin B COOH-terminal heptapeptides were synthesized in order to examine the effect of ligand dimerization on the receptor selection. Dimerization was carried out at the NH2-terminus of peptides with succinic acid, yielding succinyl bis[Asp-Ser-Phe-Val-Gly-Leu-Met-NH2] (D-NKA4-10) and succinyl bis[Asp-Phe-Phe-Val-Gly-Leu-Met-NH2] (D-NKB4-10). In the assay using rat vas deferens (RVD), it was found that the deletion of the NH2-terminal tripeptide from native neurokinin A or B enhances the activity 1.5- to 8-fold, resulting in formation of NK-2 receptor specific ligands NKA4-10 and NKB4-10. When dimeric analogs of these shortened peptides, namely D-NKA4-10 and D-NKB4-10, were examined in RVD and guinea pig ileum (GPI), they were fairly potent in GPI, but not in RVD. Under conditions in which the NK-1 receptors in GPI were desensitized with NK-1 specific substance P methyl ester, dimers reduced the activity drastically, while the corresponding monomers exhibited unchanged activity. These results suggest that dimerization of the COOH-terminal heptapeptide of neurokinins changes the receptor selection of peptides from NK-2 to NK-1, and that the NK-1 receptor has a structure favorable to a dimeric peptide ligand.
authors.affiliation: Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: H
authors.initials: H
authors.lastname: Kodama
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Takano
authors.forename: H
authors.initials: H
authors.lastname: Kamiya
authors.forename: M
authors.initials: M
authors.lastname: Waki
authors.forename: Y
authors.initials: Y
authors.lastname: Shimohigashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D046911:Macromolecular Substances; D009842:Oligopeptides; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D013373:Substance P; D015288:Neurokinin A; D002217:Carbachol