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

• DOI: 10.1039/c9md00538b
• Publication Date: 2020-01-20T08:03:39Z
• Authors: Jonas Buschmann; Theresa Seiler; Günther Bernhardt; Max Keller; David Wifling
• Keywords: 0301 basic medicine; 03 medical and health sciences

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