The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety

Ho, Guo Jie; Anthes, John C.; Bercovici, Ana; Caldwell, John P.; Cheng, Kui; Cui, Xiaoming; Fawzi, Ahmad; Fernandez, Xiomara; Greenlee, William J.; Hey, John A.; Korfmacher, Walter A.; Lu, Shao Chun; McLeod, Robbie L.; Ng, Fay W.; Torhan, April Smith; Tan, Zheng Lin; Tulshian, Deen; Varty, Geoffrey B.; Xu, Xiaoying; Zhang, Hongtao

doi:10.1016/j.bmcl.2009.03.031

Cited by 25 publications

(17 citation statements)

References 24 publications

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“…Indeed, in safety pharmacology rat studies SCH 486757 did not affect blood gases or respiratory function parameters at oral doses up to 30 mg/kg (data not shown). Taken together, our studies are consistent with previous experiments indicating that NOP receptor agonists, the endogenous peptide nociceptin/orphanin FQ and small molecules, from varying chemical structures, are effective in inhibiting cough in experimental models (McLeod et al, 2001, 2004, 2009; Bolser et al, 2001; Lee et al, 2006; Ho et al, 2009; Yang et al, 2009). …”

Section: Discussionsupporting

confidence: 92%

Pharmacological profile of the NOP agonist and cough suppressing agent SCH 486757 (8-[Bis(2-Chlorophenyl)Methyl]-3-(2-Pyrimidinyl)-8-Azabicyclo[3.2.1]Octan-3-Ol) in preclinical models

McLeod¹,

Tulshian²,

Bolser

et al. 2010

European Journal of Pharmacology

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We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/ orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K i = 4.6 ± 0.61 nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1 mg/kg) suppressed cough at 2, 4, and 6 h post oral administration with a maximum efficacy occurring at 4 h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0 mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12 mg/kg, i.p.) but not by naltrexone (10 mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1 mg/kg) inhibited capsaicin-evoked coughing by 46 ±9% and 40 ± 11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10 mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models.

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Section: Discussionsupporting

confidence: 92%

Pharmacological profile of the NOP agonist and cough suppressing agent SCH 486757 (8-[Bis(2-Chlorophenyl)Methyl]-3-(2-Pyrimidinyl)-8-Azabicyclo[3.2.1]Octan-3-Ol) in preclinical models

McLeod¹,

Tulshian²,

Bolser

et al. 2010

European Journal of Pharmacology

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“…107 These two NOP agonists were characterized extensively by Schering-Plough in rodent models of anxiety, 73,108 both in rat and mouse, and found to have robust anxiolytic profiles, in a variety of anxiety paradigms, similar to that observed with 8 . Notably, the anxiolytic efficacy of 12 and 13 was observed at doses at which there was no nonspecific disruption of activity, as was observed with classical benzodiazepines.…”

Section: Introductionmentioning

confidence: 94%

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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“…In addition to inhibiting chemical irritantprovoked cough in guinea pigs, nociceptin/orphanin FQ blocks cough produced by mechanical perturbation of the trachea in the cat [17] . Follow-up experiments with various nonpeptide NOP agonists supported the position that this pharmacological class of drug suppresses cough in animal models [18][19][20][21] .…”

Section: Preclinical Perspective Of Sch 486757 In Animal Models Of Coughmentioning

confidence: 96%

Where Are the New Cough Treatments: A Debriefing of Recent Clinical Proof-of-Concept Trials with the NOP Agonist SCH 486757

McLeod¹,

Tulshian²,

Sadeh

2011

Pharmacology

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Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable ‘road map’ that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.

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The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety

Cited by 25 publications

References 24 publications

Pharmacological profile of the NOP agonist and cough suppressing agent SCH 486757 (8-[Bis(2-Chlorophenyl)Methyl]-3-(2-Pyrimidinyl)-8-Azabicyclo[3.2.1]Octan-3-Ol) in preclinical models

Pharmacological profile of the NOP agonist and cough suppressing agent SCH 486757 (8-[Bis(2-Chlorophenyl)Methyl]-3-(2-Pyrimidinyl)-8-Azabicyclo[3.2.1]Octan-3-Ol) in preclinical models

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

Where Are the New Cough Treatments: A Debriefing of Recent Clinical Proof-of-Concept Trials with the NOP Agonist SCH 486757

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