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

Abstract

Background and purpose: d-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.

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

“…Interestingly, at the same dose 4 and 10 provided opposite behavioural effects; namely 4 caused excessive grooming and agitation (constant, fast moving in the cage, burrowing in the nesting material), while with 10 the mice appeared sedated, quiet, easily handled, and moving slowly if at all. Furthermore, 4 did not induce convulsions even at the highest doses, confirming our previous data on its antidepressant and anxiolytic studies,9, 10 which are in accord with observations about the higher convulsive effects of the nonpeptidic δ agonists in comparison to opioid peptides 26, 31, 32…”

Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

“…UFP-512 (H-Dmt-Tic-NH-CH(CH2–COOH)-Bid), a specific and potent DOR agonist [44–46], was synthesized by our research team. UFP-512 was dissolved in water with a stock concentration of 10 mM, and stored at −80 °C.…”

ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands

“…Radioligand binding studies were performed on attached cells as described previously [17]. Each determination was carried out in triplicate.…”

“…Inhibition of adenylate cyclase was determined by measuring [ 3 H] cAMP accumulation as previously described [17]. Maximal inhibitory levels of opioid agonists were determined for each clonal cell line at 0.1X, 1X and 10X of the concentration producing the maximum response in the non-transfected SK-N-BE (BE-WT) cells [13].…”