Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)

Chang, Steven D.; Brieaddy, Lawrence E.; Harvey, Joseph D.; Lewin, Anita H.; Mascarella, S. Wayne; Seltzman, Herbert H.; Reddy, P. Anantha; Decker, Ann M.; McElhinny, Charles J.; Zhong, Desong; Peterson, Elisha E.; Navarro, Hernán A.; Bruchas, Michael R.; Carroll, F. Ivy

doi:10.1021/acschemneuro.5b00208

Cited by 16 publications

(13 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comparing the ligand efficacy at G protein and β-arrestin 2 suggests that Ro 65-6570 behaved as a G protein-biased agonist. This seems to be the rule for NOP (Malfacini et al, 2015; Chang et al, 2015b, 2015a) and opioid (Molinari et al, 2010) nonpeptide agonists. AT-090 and AT-127 seem to be the exception to this rule.…”

Section: Discussionmentioning

confidence: 94%

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations

Ferrari

Cerlesi

Malfacini

et al. 2016

European Journal of Pharmacology

View full text Add to dashboard Cite

Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [35S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65-6570) and the NOP selective antagonist SB-612111. AT compounds displayed high NOP affinity and behaved as NOP agonists in all the functional assays consistently showing the following rank order of potency AT-127≥AT-090≥AT-035 > AT-004= AT-001. AT compounds behaved as NOP full agonists in the calcium mobilization and mouse colon assays and as partial agonists in the [35S]GTPγS and BRET assays. Interestingly AT-090 and AT-127, contrary to standard nonpeptide agonists that display G protein biased agonism, behaved as an unbiased agonists. AT-090 and AT-127 displayed higher NOP selectivity than Ro 65-6570 at native mouse receptors. AT-090 and AT-127 might be useful pharmacological tools for investigating the therapeutic potential of NOP partial agonists.

show abstract

Section: Discussionmentioning

confidence: 94%

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations

Ferrari

Cerlesi

Malfacini

et al. 2016

European Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

“…N/OFQ, Ro64‐6198 and Ro65‐6570 have no or only a weak bias for G‐protein signaling (Chang et al . ; Rizzi et al . ); thus, the lack of β‐arrestin2 signaling is an attractive hypothesis to explain the better tolerability of cebranopadol as compared to other NOP receptor agonists and may also give first hints regarding a possible functional relevance of biased signaling at the NOP receptor.…”

Section: Discussionmentioning

confidence: 99%

Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents

et al. 2017

View full text Add to dashboard Cite

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4-week subacute administration. Naloxone-precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1-week re-administration following the spontaneous withdrawal period. In both tests, cebranopadol-treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid-type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.

show abstract

“…A number of studies suggest that the systemic injection of Ro 64-6198 does not modify nociceptive pain transmission in rodents, as demonstrated in the tail flick, tail immersion, tactile or cold water stimulation, and foot shock test Obara et al, 2005;Varty et al, 2005;Reiss et al, 2008). However an exception to this rule is the mouse hot plate test where systemic Ro 64-6198 produced modest antinociceptive effects (Reiss et al, 2008;Chang et al, 2015a). These effects were reproduced in NOP(+/+) but not NOP(2/2) mice.…”

Section: B Nociceptin/orphanin Fq Unrelated Peptidesmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

Self Cite

View full text Add to dashboard Cite

The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

show abstract

Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)

Cited by 16 publications

References 32 publications

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations

Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Contact Info

Product

Resources

About