Selective mode of action of guanidine-containing non-peptides at human NPFF receptors.
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.
Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Brüderstrasse 34, D-04103 Leipzig, Germany.
Maria
M
Findeisen
Cäcilia
C
Würker
Daniel
D
Rathmann
René
R
Meier
Jens
J
Meiler
Roger
R
Olsson
Annette G
AG
Beck-Sickinger
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D001681:Biological Assay; D019556:COS Cells; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D019791:Guanidine / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008856:Microscopy, Fluorescence; D008968:Molecular Conformation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
C092926:BIBP 3226; D004151:Dipeptides; D008024:Ligands; D057786:Peptidomimetics; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C508361:adamantylcarbonyl-arginyl-phenylalaninamide; C083929:neuropeptide FF receptor; D001120:Arginine; D019791:Guanidine; D000218:Adamantane