Design and synthesis of dimeric analogs of neurokinin A and B: effect of dimerization of COOH-terminal heptapeptides on receptor selection
Sakaguchi, K.; Kodama, H.; Matsumoto, H.; Yoshida, M.; Takano, Y.; Kamiya, H.; Waki, M.; Shimohigashi, Y.
Peptide Research 2(5): 345-351
1989
ISSN/ISBN: 1040-5704 PMID: 2485210 Document Number: 345078
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.