Argininamide-type neuropeptide Y Y₁ receptor antagonists: the nature of N ^ω-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 (pK _i: 10.11), argininamide-type Y₁R antagonist UR-MK299 (2), revealed that the N ^ω-carbamoyl substituent (van der Waals volume: 139 ų) 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 ų), the ligands bound in an inverted mode with the carbamoyl side chain located at the surfa

SUBMITTER: Buschmann J 

PROVIDER: S-EPMC7536821 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature