Modular synthesis of non-peptidic bivalent NPY Y1 receptor antagonists.
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.
Institut für Organische Chemie, Universität Regensburg, D-93040 Regensburg, Germany.
Stefan
S
Weiss
Max
M
Keller
Günther
G
Bernhardt
Armin
A
Buschauer
Burkhard
B
König
D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009478:Neuropeptide Y / Q000737:chemistry / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism
D014151:Anti-Anxiety Agents; C092926:BIBP 3226; D008024:Ligands; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D001120:Arginine; D002118:Calcium