期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 22, 页码 9858-9866出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.09.033
关键词
Neuropeptide Y; Bivalent ligands; Guanidinium compounds; Binding; Huisgen reaction; Cycloaddition
资金
- Deutsche Forschungsgemeinschaft [GRK 760]
According to a 'bivalent ligand approach' to increase the affinity of the potent argininamide-type NPY Y-1 receptor antagonist BIBP-3226, dimeric ligands were synthesized in which two molecules of the parent compound were linked by different spacers via N-G-acylation at the guanidino groups. A synthetic route for the preparation of the title compounds was developed, which includes a copper(I)-catalyzed azide alkyne cycloaddition as the key step. Three bivalent analogues of BIBP-3226 were prepared showing nanomolar antagonistic activity and binding affinity to the NPY Y1 receptor (calcium assay on HEL cells, radioligand binding assay on SK-N-MC cells), but these ligands were not superior to the parent compound and there was no correlation with the length or the chemical nature of the spacer. A trivalent BIBP-3226 derivate showed, surprisingly, no affinity to the NPY Y-1 receptor at all. (C) 2008 Elsevier Ltd. All rights reserved.
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