title: In vitro and in vivo pharmacological profile of UFP-512, a novel selective delta-opioid receptor agonist; correlations between desensitization and tolerance.
abstract: OBJECTIVE
  Delta-opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance.
  
  
  METHODS
  Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test.
  
  
  RESULTS
  In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration.
  
  
  CONCLUSIONS
  There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders.
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire de la Signalisation, UPRES-EA 3919, IFR 146 ICORE, Université de Caen, Caen, France.
authors.forename: B
authors.initials: B
authors.lastname: Aguila
authors.forename: L
authors.initials: L
authors.lastname: Coulbault
authors.forename: M
authors.initials: M
authors.lastname: Boulouard
authors.forename: F
authors.initials: F
authors.lastname: Léveillé
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: G
authors.initials: G
authors.lastname: Tóth
authors.forename: A
authors.initials: A
authors.lastname: Borsodi
authors.forename: G
authors.initials: G
authors.lastname: Balboni
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.forename: P
authors.initials: P
authors.lastname: Jauzac
authors.forename: S
authors.initials: S
authors.lastname: Allouche
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D008130:Lomustine / Q000378:metabolism; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008942:Mitoxantrone / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011241:Prednisone / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013550:Swimming
chemical_list: C526539:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide; D000928:Antidepressive Agents; D001562:Benzimidazoles; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D003561:Cytarabine; D008130:Lomustine; D008942:Mitoxantrone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011241:Prednisone