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

Jonas Buschmann; Theresa Seiler; Günther Bernhardt; Max Keller; David Wifling

doi:10.1039/c9md00538b

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

RSC Med Chem. 2020 Jan 20;11(2):274-282. doi: 10.1039/c9md00538b. eCollection 2020 Feb 1.

Authors

Jonas Buschmann¹, Theresa Seiler¹, Günther Bernhardt¹, Max Keller¹, David Wifling¹

Affiliation

¹ Institute of Pharmacy , Faculty of Chemistry and Pharmacy , University of Regensburg , Universitätsstrasse 31 , D-93053 Regensburg , Germany . Email: david.wifling@ur.de.

Abstract

The recently resolved crystal structure of the neuropeptide Y Y₁ receptor (Y₁R), co-crystallized with the high-affinity (pK _i: 10.11), argininamide-type Y₁R antagonist UR-MK299 (2), revealed that the N ^ω-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 pK _i: 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.