Argininamide-type neuropeptide Y Y receptor antagonists: the nature of -carbamoyl substituents determines YR binding mode and affinity.

The recently resolved crystal structure of the neuropeptide Y Y receptor (YR), co-crystallized with the high-affinity (p : 10.11), argininamide-type YR antagonist UR-MK299 (), revealed that the -carbamoyl substituent (van der Waals volume: 139 Å) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to . YR affinity decreased with increasing size of the carbamoyl residue (minimal p : 5.67). Exceeding a critical size of the substituent (van der Waals volume: 212 Å), 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.