In vitro and in vivo pharmacological profile of UFP-512, a novel selective delta-opioid receptor agonist; correlations between desensitization and tolerance.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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: B Aguila, L Coulbault, M Boulouard, F Léveillé, A Davis, G Tóth, A Borsodi, G Balboni, S Salvadori, P Jauzac, S Allouche
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 8 Pg. 1312-24 (Dec 2007) ISSN: 0007-1188 [Print] England
• PMID: 17982482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide
• Antidepressive Agents
• Benzimidazoles
• Oligopeptides
• Receptors, Opioid, delta
• Cytarabine
• Lomustine
• Mitoxantrone
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Prednisone

Topics

• Animals
• Antidepressive Agents (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (metabolism)
• Benzimidazoles (administration & dosage, pharmacology)
• Binding, Competitive
• Cell Line, Tumor
• Cytarabine (metabolism)
• Depression (drug therapy)
• Desensitization, Immunologic
• Disease Models, Animal
• Drug Administration Schedule
• Drug Tolerance
• Endocytosis (drug effects)
• Humans
• Lomustine (metabolism)
• Male
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mitoxantrone (metabolism)
• Neuroblastoma (metabolism)
• Oligopeptides (administration & dosage, pharmacology)
• Phosphorylation (drug effects)
• Prednisone (metabolism)
• Receptors, Opioid, delta (agonists)
• Signal Transduction (drug effects)
• Swimming