Issue 2, 2020

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

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

Supplementary files

Article information

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

RSC Med. Chem., 2020,11, 274-282

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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