Discovery and Structure−Activity Relationship of Quinuclidine Benzamides as Agonists of α7 Nicotinic Acetylcholine Receptors

Bodnar, Alice L.; Cortes-Burgos, Luz A.; Cook, Karen K.; Dinh, Dac M.; Groppi, Vincent E.; Hajós, Mihály; Higdon, Nicole R.; Hoffmann, William E.; Hurst, Raymond S; Myers, Jason K.; Rogers, Bruce N.; Wall, Theron M.; Wolfe, Mark L.; Wong, Erik H. F.

doi:10.1021/jm049363q

Cited by 206 publications

(176 citation statements)

References 23 publications

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“…Results from these studies suggest that reversal of our 6 hour delay-induced deficit, by PNU-282987 and RJR-2403, is mediated via activation of the hippocampus. PNU-282987 is a selective agonist of the human and rat α7 nAChR (Bodnar et al, 2005;Hajós et al, 2005); and RJR-2403 is an agonist with high selectivity and potency for α4β2 nAChR (Lippiello et al, 1996). Both α7 and α4β2 nicotinic receptors are found in the rat hippocampus (Séguéla et al, 1993;Wada et al, 1989) and are believed to contribute to the release of acetylcholine and glutamate (Changeux et al, 1998;Mansvelder et al, 2002;Wonnacott, 1997).…”

Section: Discussionmentioning

confidence: 99%

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

McLean

Grayson

Marsh

et al. 2016

Behavioural Brain Research

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In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female hooded-Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6 hour inter-trial interval (ITI). In all treatment groups there was no preference for the left or right identical objects in the acquisition trial. In the retention trial vehicle, risperidone (0.16mg/kg), PNU-282987, an α7 agonist (5mg/kg) and RJR-2403, an α4β2 agonist (1mg/kg) treated rats were unable to discriminate between the novel and familiar objects following a 6 hour ITI. In contrast, donepezil (1.0mg/kg), PNU-282987 (10mg/kg) and RJR-2403 (0.1mg/kg) treated rats spent significantly more time exploring the novel compared to the familiar object following the 6 hour ITI, indicative of enhanced cognitive performance (P<0.05-P<0.01). Interestingly, these compounds were efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.

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Section: Discussionmentioning

confidence: 99%

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

McLean

Grayson

Marsh

et al. 2016

Behavioural Brain Research

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show abstract

“…7 ) [117, 118]. PNU-282987 binds to α7 nAChR with a K i of 27 nM, and showed evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective α7 nAChR antagonist MLA [117, 118].…”

Section: α7 Nicotinic Receptor Agonistsmentioning

confidence: 99%

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Toyohara¹,

Hashimoto²

2010

Open Med Chem J

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Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs.

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“…) that improve cognitive functions in experimental animals models (Bodnar et al, 2005;Leonik et al, 2007). A novel set of azabicyclic aryl amides to improve the properties of PNU-282987 were recently identified as selective alpha7nAChR-agonist with a potential for treating cognitive deficits (Walker et al, 2006).…”

Section: Alpha7nachr-agonists and Allosteric Modulators In Neurodegenmentioning

confidence: 99%

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

Conejero-Goldberg

Davies

Ulloa

2008

Neuroscience & Biobehavioral Reviews

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Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

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Discovery and Structure−Activity Relationship of Quinuclidine Benzamides as Agonists of α7 Nicotinic Acetylcholine Receptors

Cited by 206 publications

References 23 publications

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

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