title: Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226.
abstract: Neuropeptide FF (NPFF) is a part of a neurotransmitter system acting as a modulator of endogenous opioid functions. At this time, no non-peptide or peptide NPFF-antagonists have been discovered. Here, we demonstrate that Neuropeptide Y (NPY) ligands, in fact possess significant ability to interact with the human NPFF(2) receptors. NPY Y(1) antagonist BIBP3226 and mixed Y(1) antagonist/Y(4) agonist GR231118 are able to displace with low affinity, 50 -- 100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an affinity however superior to those determined against Y(2), Y(4) or Y(5) receptors. Furthermore, BIBP3226 which is unable to inhibit the forskolin-stimulated cyclic AMP production mediated by NPFF(2) receptors, antagonizes the effect of NPFF, revealing the first antagonist of NPFF receptors. These properties of NPY ligands on Neuropeptide FF receptors must be considered when evaluating pharmacological activities of these drugs.
authors.affiliation: Institut de Pharmacologie et Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Mollereau
authors.forename: C
authors.initials: C
authors.lastname: Gouardères
authors.forename: Y
authors.initials: Y
authors.lastname: Dumont
authors.forename: M
authors.initials: M
authors.lastname: Kotani
authors.forename: M
authors.initials: M
authors.lastname: Detheux
authors.forename: H
authors.initials: H
authors.lastname: Doods
authors.forename: M
authors.initials: M
authors.lastname: Parmentier
authors.forename: R
authors.initials: R
authors.lastname: Quirion
authors.forename: J M
authors.initials: JM
authors.lastname: Zajac
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: C097287:1229U91; D014151:Anti-Anxiety Agents; C092926:BIBP 3226; D008024:Ligands; D010456:Peptides, Cyclic; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D005576:Colforsin; D001120:Arginine; D000242:Cyclic AMP