Premium
In vitro and in vivo pharmacological profile of UFP‐512, a novel selective δ‐opioid receptor agonist; correlations between desensitization and tolerance
Author(s) -
Aguila B,
Coulbault L,
Boulouard M,
Lιveillι F,
Davis A,
Tσth G,
Borsodi A,
Balboni G,
Salvadori S,
Jauzac P,
Allouche S
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707497
Subject(s) - receptor , agonist , pharmacology , desensitization (medicine) , chemistry , in vivo , functional selectivity , opioid , biology , biochemistry , microbiology and biotechnology
Background and purpose: δ‐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(CH 2 ‐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 Ser 363 , 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. British Journal of Pharmacology (2007) 152 , 1312–1324; doi: 10.1038/sj.bjp.0707497 ; published online 5 November 2007