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Issue 2, 2020
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Argininamide-type neuropeptide Y Y1 receptor antagonists: the nature of Nω-carbamoyl substituents determines Y1R binding mode and affinity

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Abstract

The recently resolved crystal structure of the neuropeptide Y Y1 receptor (Y1R), co-crystallized with the high-affinity (pKi: 10.11), argininamide-type Y1R antagonist UR-MK299 (2), revealed that the Nω-carbamoyl substituent (van der Waals volume: 139 Å3) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to 2. Y1R affinity decreased with increasing size of the carbamoyl residue (minimal pKi: 5.67). Exceeding a critical size of the substituent (van der Waals volume: 212 Å3), the ligands bound in an inverted mode with the carbamoyl side chain located at the surface of the receptor, as suggested by induced-fit docking and MD simulations.

Graphical abstract: Argininamide-type neuropeptide Y Y1 receptor antagonists: the nature of Nω-carbamoyl substituents determines Y1R binding mode and affinity

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Supplementary files

Article information


Submitted
15 Nov 2019
Accepted
30 Dec 2019
First published
20 Jan 2020

RSC Med. Chem., 2020,11, 274-282
Article type
Research Article

Argininamide-type neuropeptide Y Y1 receptor antagonists: the nature of Nω-carbamoyl substituents determines Y1R binding mode and affinity

J. Buschmann, T. Seiler, G. Bernhardt, M. Keller and D. Wifling, RSC Med. Chem., 2020, 11, 274
DOI: 10.1039/C9MD00538B

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