Selective mode of action of guanidine-containing non-peptides at human NPFF receptors.

Findeisen M, W├╝rker C, Rathmann D, Meier R, Meiler J, Olsson R, Beck-Sickinger AG
J Med Chem. 2012 55 (13): 6124-36

PMID: 22708927 · PMCID: PMC3404467 · DOI:10.1021/jm300535s

The binding pocket of both NPFF receptors was investigated, focusing on subtype-selective behavior. By use of four nonpeptidic compounds and the peptide mimetics RF9 and BIBP3226, agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated. The binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF(1) but not in the NPFF(2) receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system.

MeSH Terms (20)

Adamantane Amino Acid Substitution Animals Arginine Binding Sites Biological Assay Chlorocebus aethiops COS Cells Dipeptides Drug Design Guanidine HEK293 Cells Humans Ligands Microscopy, Fluorescence Molecular Conformation Peptidomimetics Receptors, G-Protein-Coupled Receptors, Neuropeptide Structure-Activity Relationship

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