| Item type: | Article | ||||||
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| Journal or Publication Title: | ChemMedChem | ||||||
| Publisher: | WILEY-BLACKWELL | ||||||
| Place of Publication: | MALDEN | ||||||
| Volume: | 4 | ||||||
| Number of Issue or Book Chapter: | 10 | ||||||
| Page Range: | pp. 1733-1745 | ||||||
| Date: | 11 August 2009 | ||||||
| Additional Information (public): | Supporting Information available | ||||||
| Institutions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) | ||||||
| Projects (Historical): | GRK 760, Graduiertenkolleg Medizinische Chemie | ||||||
| Identification Number: |
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| Related URLs: |
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| Keywords: | PROTEIN-COUPLED RECEPTORS; KAPPA-OPIOID RECEPTORS; HIGHLY POTENT; LIGANDS; CELLS; AFFINITY; DELTA; BENEXTRAMINE; LUMINESCENCE; EXPRESSION; antagonists; bridging ligands; dimerization; neuropeptide Y; receptors | ||||||
| Dewey Decimal Classification: | 500 Science > 540 Chemistry & allied sciences 500 Science > 540 Chemistry & allied sciences | ||||||
| Status: | Published | ||||||
| Refereed: | Yes, this version has been refereed | ||||||
| Created at the University of Regensburg: | Yes | ||||||
| Item ID: | 6926 |
Web of ScienceAbstract
Bivalent ligands are potential tools to investigate the dimerisation of G-protein-coupled receptors. Based on the (R)-argininamide BIBP 3226, a potent and selective neuropeptide Y Y-1 receptor (Y1R) antagonist, we prepared a series of bivalent Y1R ligands with a wide range of linker lengths (8-36 atoms). Exploiting the high eudismic ratio (>1000) of the parent compound, we synthesised sets of ...
Abstract
Bivalent ligands are potential tools to investigate the dimerisation of G-protein-coupled receptors. Based on the (R)-argininamide BIBP 3226, a potent and selective neuropeptide Y Y-1 receptor (Y1R) antagonist, we prepared a series of bivalent Y1R ligands with a wide range of linker lengths (8-36 atoms). Exploiting the high eudismic ratio (>1000) of the parent compound, we synthesised sets of R,R-, R,S- and S,S-configured bivalent ligands to gain insight into the "bridging" of two Y(1)Rs by simultaneous interaction with both binding sites of a putative receptor dimer. Except for the S,S isomers, the bivalent ligands are high-affinity Y1R antagonists, as determined by Ca2+ assays on HEL cells and radioligand competition assays on human Y1R-expressing SK-N-MC and MCF-7 cells. Whereas the R,R enantiomers are most potent, no marked differences were observed relative to the corresponding mesa forms. The difference between R,R and R,S diastereomers was most pronounced (about sixfold) in the case of the Y1R antagonist containing a spacer of 20 atoms in length. Among the R,R enantiomers, linker length and structural diversity had little effect on Y1R affinity. Although the bivalent ligands preferentially bind to the Y1R, the selectivity toward human Y-2, Y-4, and Y-5 receptors was markedly lower than that of the monovalent argininamides. The results of this study neither support the presence of Y1R dimers nor the simultaneous occupation of both binding pockets by the twin compounds. However, as the interaction with Y1R dimers cannot be unequivocally ruled out, the preparation of a bivalent radioligand is suggested to determine the ligand-receptor stoichiometry. Aiming at such radio-labelled pharmacological tools, prototype twin compounds were synthesised, containing an N-propionylated amino-functionalised branched linker (K-i >= 18 nM), a tritiated form of which can be easily prepared.
Metadata last modified: 29 Sep 2021 07:30
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