Abstract
The recently resolved crystal structure of the neuropeptide Y Y-1 receptor (Y1R), co-crystallized with the high-affinity (pK(i): 10.11), argininamide-type Y1R antagonist UR-MK299 (2), revealed that the N-omega-carbamoyl substituent (van der Waals volume: 139 angstrom(3)) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, ...
Abstract
The recently resolved crystal structure of the neuropeptide Y Y-1 receptor (Y1R), co-crystallized with the high-affinity (pK(i): 10.11), argininamide-type Y1R antagonist UR-MK299 (2), revealed that the N-omega-carbamoyl substituent (van der Waals volume: 139 angstrom(3)) 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 angstrom(3)), 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.
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