Keller, Max and Weiss, Stefan and Hutzler, Christoph and Kuhn, Kilian K. and Mollereau, Catherine and Dukorn, Stefanie and Schindler, Lisa and Bernhardt, Gunther and Konig, Burkhard and Buschauer, Armin (2015) N-omega-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y-1 Receptor Antagonists and a Radio labeled Selective High-Affinity Molecular Tool ([H-3]UR-MK299) with Extended Residence Time. JOURNAL OF MEDICINAL CHEMISTRY, 58 (22). pp. 8834-8849. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
Analogues of the argininamide-type NPY Y-1 receptor (Y1R) antagonist BIBP3226, bearing carbamoyl moieties at the guanidine group, revealed subnanomolar Ki values and caused depression of the maximal response to NPY (calcium assay) by up to 90% in a concentration- and time-dependent manner, suggesting insurmountable antagonism. To gain insight into the mechanism of binding of the synthesized compounds, a tritiated antagonist, (R)-N-a-diphenylacetyl-N-omega-[2-([2,3-H-3]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([H-3]UR-MK299, [H-3]38), was prepared. [H-3]38 revealed a dissociation constant in the picomolar range (K-d 0.044 nM, SK-N-MC cells) and very high Y1R selectivity. Apart from superior affinity, a considerably lower target off-rate (t1/2 95 min) was characteristic of [H-3]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t(1/2) 3 min, K-d 2.0 nM). Y1R binding of [H-3]38 was fully reversible and fully displaceable by nonpeptide antagonists and the agonist pNPY. Therefore, the insurmountable antagonism observed in the functional assay has to be attributed to the extended target-residence time, a phenomenon of relevance in drug research beyond the NPY receptor field.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACYLGUANIDINE BIOISOSTERIC APPROACH; NEUROPEPTIDE-Y; CANCER; POTENT; RADIOLIGAND; INHIBITION; LIGANDS; DESIGN; CELLS; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2019 08:13 |
| Last Modified: | 06 May 2019 08:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4440 |
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