In vitro and in vivo pharmacological profile of UFP-512, a novel selective delta-opioid receptor agonist; correlations between desensitization and tolerance.
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.
Aguila
B
B
Laboratoire de Biologie Cellulaire et Moléculaire de la Signalisation, UPRES-EA 3919, IFR 146 ICORE, Université de Caen, Caen, France.
Coulbault
L
L
Boulouard
M
M
Léveillé
F
F
Davis
A
A
Tóth
G
G
Borsodi
A
A
Balboni
G
G
Salvadori
S
S
Jauzac
P
P
Allouche
S
S
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
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