Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist

Abstract

The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G‐proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G‐protein and β‐arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G‐protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP–β‐arrestin 2 interactions and displayed reduced potency at mu/β‐arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long‐lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB‐612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)

“…In line with previous findings (Malfacini et al, 2015; Rizzi et al, 2016), the standard peptides N/OFQ and dermorphin behaved as potent and selective agonists in promoting receptor interaction both with G protein and β-arrestin 2. [Dmt 1 ]N/OFQ(1-13)-NH 2 was able to similarly promote receptor interaction with G protein and β-arrestin at NOP and mu receptors.…”

“…The PWT derivative of such ligand may promote robust and long lasting analgesic effects based on the well described synergistic action of NOP and mu receptor activation (reviewed in Toll et al (2016)). The promising results obtained with the mixed agonist cebranopadol (Schunk et al, 2014) in preclinical (Linz et al, 2014; Rizzi et al, 2016) as well as clinical studies (Lambert et al, 2015) corroborate this proposal.…”

“…The BRET assay used to investigate the ability of [Dmt 1 ]N/OFQ(1-13)-NH 2 and PWT2-[Dmt 1 ] to promote receptor interaction with G protein and β-arrestin 2 has been previously validated for classical opioid (Molinari et al, 2010) as well as NOP receptors (Malfacini et al, 2015) and then used for characterizing novel ligands (Asth et al, 2016; Bird et al, 2016; Rizzi et al, 2016) or for selecting the best compounds for inducing receptor stability and crystallogenesis (Miller et al, 2015). In line with previous findings (Malfacini et al, 2015; Rizzi et al, 2016), the standard peptides N/OFQ and dermorphin behaved as potent and selective agonists in promoting receptor interaction both with G protein and β-arrestin 2.…”

In vitro pharmacological characterization of a novel unbiased NOP receptor‐selective nonpeptide agonist AT‐403

“…; Rizzi et al. ). We used the BRET‐based assay to characterize the functional selectivity of the nonpeptide NOP full agonists for the G‐protein or arrestin pathway.…”

“…; Rizzi et al. ). Similar findings have also been reported for mu and delta opioid receptor nonpeptide agonists (Molinari et al.…”