Weiss, Stefan and Keller, Max and Bernhardt, Günther and Buschauer, Armin and König, Burkhard (2008) Modular synthesis of non-peptidic bivalent NPY Y(1) receptor antagonists. Bioorganic & Medicinal Chemistry 16 (22), pp. 9858-9866.
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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 Y(1) 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.
|Date:||13 September 2008|
|Institutions:|| Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König|
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Keywords:||bivalent ligands; neuropeptide Y; NPY; Y1 receptor antagonist; argininamides; BIBP 3226; guanidinium compounds; Huisgen reaction; cycloaddition|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||29 Oct 2008 21:05|
|Last Modified:||08 Nov 2010 10:18|