title: Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists.
abstract: Neuropeptide FF (NPFF) belongs to an opioid-modulatory system including two precursors (pro-NPFF(A) and pro-NPFF(B)) and two G-protein coupled receptors (NPFF(1) and NPFF(2)). The pharmacological and functional profiles of human NPFF(1) and NPFF(2) receptors expressed in Chinese hamster ovary (CHO) cells were compared by determining the affinity of several peptides derived from both NPFF precursors and by measuring their abilities to inhibit forskolin-induced cAMP accumulation. Each NPFF receptor recognizes peptides from both precursors with nanomolar affinities, however, with a slight preference of pro-NPFF(A) peptides for NPFF(2) receptors and of pro-NPFF(B) peptides for NPFF(1) receptors. BIBP3226 ((R)-N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-argininamide) and BIBO3304 ((R)-N(2)-(diphenylacetyl)-N-[4-(aminocarbonylaminomethyl)-benzyl]-argininamide trifluoroacetate), two selective neuropeptide Y (NPY) Y(1) receptor antagonists, display relative high affinities for NPFF receptors and exhibit antagonist properties towards hNPFF(1) receptors. The structural determinants responsible for binding of these molecules to NPFF receptors were investigated and led to the synthesis of hNPFF(1) receptor antagonists with affinities from 40 to 80 nM. Our results demonstrate differences in pharmacological characteristics between NPFF(1) and NPFF(2) receptors and the feasibility of subtype-selective antagonists.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (CNRS, UMR5089), 205 route de Narbonne, 31077 Toulouse cedex 04, France. catherine.mollereau-manaute@ipbs.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.forename: Honoré
authors.initials: H
authors.lastname: Mazarguil
authors.forename: Delphine
authors.initials: D
authors.lastname: Marcus
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quelven
authors.forename: Masato
authors.initials: M
authors.lastname: Kotani
authors.forename: Vincent
authors.initials: V
authors.lastname: Lannoy
authors.forename: Yvan
authors.initials: Y
authors.lastname: Dumont
authors.forename: Rémi
authors.initials: R
authors.lastname: Quirion
authors.forename: Michel
authors.initials: M
authors.lastname: Detheux
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Zajac
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D018013:Receptors, Neuropeptide / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C092926:BIBP 3226; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D001120:Arginine; C117416:BIBO 3304