Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties

Wichmann, Jürgen; Adam, Geo; Röver, Stephan; Hennig, Michael; Scalone, Michelangelo; Cesura, Andrea M.; Dautzenberg, Frank M.; Jenck, F.

doi:10.1016/s0223-5234(00)00171-9

Cited by 100 publications

(76 citation statements)

References 18 publications

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“…The biological appreciation of the N/OFQ system has encouraged the generation of specific research tools (small molecule, peptide, and genetic) to enable preclinical investigation. Such tools have included NOP selective agonists and antagonists (Jenck et al, 2000; Röver et al, 2000; Wichmann et al, 2000; Fioravanti and Vanderah, 2008; Przydzial and Heisler, 2008; Chiou et al, 2010; Largent-Milnes and Vanderah, 2010; Zaveri, 2011), N/OFQ-deficient mice (Koster et al, 1999; Kuzmin et al, 2009), and NOP receptor-deficient mice (Nishi et al, 1997), and rats (Homberg et al, 2009; Rizzi et al, 2011). In contrast, few studies have explored the effects of modifying the synthesis and/or metabolic disposition of N/OFQ.…”

Section: Introductionmentioning

confidence: 99%

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Witkin

Statnick

Rorick-Kehn

et al. 2014

Pharmacology & Therapeutics

179

162

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Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of nociceptin. In addition, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present commentary focuses on the role of N/OFQ in the regulation of feeding and body weight homeostasis, stress and the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.

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Section: Introductionmentioning

confidence: 99%

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Witkin

Statnick

Rorick-Kehn

et al. 2014

Pharmacology & Therapeutics

179

162

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“…One of the first indications of the potential clinical utility of NOP agonists came from the demonstration that 8 and its congeners (e.g. 9 , Ro65-6570, 68 Figure 1, also see below) showed significant anxiolytic activity in many different assay paradigms, 50,69 later independently confirmed in a report from Schering-Plough researchers, which characterized the anxiolytic properties of 8 across three different rodent species and a variety of conditioned and unconditioned tests of anxiety. 71 …”

Section: Introductionmentioning

confidence: 95%

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

Zaveri

2016

J. Med. Chem.

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In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral) and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression and motor symptoms in Parkinson’s disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress towards validating the NOP-N/OFQ system as a therapeutic target.

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“…Ro64-6198 represents one of the most selective brain-penetrant agonist identified to date (Chiou et al, 2007; Wichmann et al, 2000). When tested in vivo following systemic administration, this agonist mimics N/OFQ disruptive actions in a range of learning tasks (Higgins et al, 2002; Sandin et al, 1997; Sandin, Ogren, & Terenius, 2004; Goeldner et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

Goeldner

Reiss

Wichmann

et al. 2009

Neurobiology of Learning and Memory

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The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.

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Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties

Cited by 100 publications

References 18 publications

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

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