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

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 A3) 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 A3), 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.