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


ABSTRACT: 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.

SUBMITTER: Findeisen M 

PROVIDER: S-EPMC3404467 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Findeisen Maria M   Würker Cäcilia C   Rathmann Daniel D   Meier René R   Meiler Jens J   Olsson Roger R   Beck-Sickinger Annette G AG  

Journal of medicinal chemistry 20120626 13


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  ...[more]

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