Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4β2 nAChRs

Grupe, Morten; Grunnet, Morten; Laursen, Bettina; Bastlund, Jesper F.

doi:10.1016/j.neuropharm.2013.12.008

Cited by 21 publications

(32 citation statements)

References 51 publications

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“…As a result, this encourages pharmacological studies addressing how positive allosteric modulation on a receptor level affects neurotransmission and ultimately cognitive behaviour in behavioural paradigms. Here, it is of key importance that such studies are conducted in a fashion that allows comparison of experimental results on these biological levels, for instance by assessing several of such levels simultaneously in the same experimental subjects to promote translatability of the findings [85,105]. Considering the diverse pharmacological profiles of the relatively few a4b2 PAMs identified so far, it will also be necessary to identify differences in the biological impact between the various PAMs.…”

Section: Discussionmentioning

confidence: 99%

“…Here, it appears that the most robust effects are seen when using compromised subjects, for example PCP-treated animals. Consistent with this idea, the lack of effect by NS9283 on task performance in a rat auditory discrimination task was speculated to be due to a ceiling effect [85]. In combination with a4b2 agonists, but not by itself, NS9283 has also displayed beneficial effects in a wide array of pre-clinical pain assays [53,83,87].…”

Section: A4b2 Nachr Pamsmentioning

confidence: 95%

“…The majority of published in vivo a4b2 PAM studies have employed NS9283, where the compound has been investigated with regard to its effects on cognition [15,51,85], pain [53,83,87] and drug discrimination [86] in rodents. The focus on this compound is, in addition to its subtype selectivity profile (table 1), due to its favourable pharmacokinetic properties with robust brain exposure and an acceptable half-life [15].…”

Section: A4b2 Nachr Pamsmentioning

confidence: 99%

“…Finally, in rats performing a simple auditory discrimination task, NS9283 was simultaneously investigated for its effect on both task performance and modulation of auditory eventrelated potentials (ERPs) [85]. Although task performance was not enhanced with NS9283, rather premature responding was increased, the amplitude of the P300-like ERP, an electrophysiological correlate of attention and working memory, was increased in mediodorsal thalamus and auditory cortex.…”

Section: Modulatory Actions Of A4b2 Pams On Neurotransmissionmentioning

confidence: 99%

“…Within certain therapeutic areas, it may also be a necessity to coadminister a PAM with another compound, as it has been observed in pain studies that NS9283 alone does not have any effect [53,83,87]. In cognition studies, NS9283 alone has demonstrated effects [15,51,85].…”

Section: Clinical Opportunities and Concerns With A4b2 Pamsmentioning

confidence: 99%

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Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

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Section: Discussionmentioning

confidence: 99%

Section: A4b2 Nachr Pamsmentioning

confidence: 95%

Section: A4b2 Nachr Pamsmentioning

confidence: 99%

Section: Modulatory Actions Of A4b2 Pams On Neurotransmissionmentioning

confidence: 99%

Section: Clinical Opportunities and Concerns With A4b2 Pamsmentioning

confidence: 99%

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Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain

Bağdaş

Ergun

Jackson

et al. 2017

European Journal of Pain

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Background: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The a4b2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of a4b2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for a4b2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at a4b2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. Methods: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotineevoked antiallodynic response. Results: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour doseand time-dependently without motor impairment. Our data revealed that this effect was mediated by the a4b2 nAChRs by using competitive a4b2 antagonist dihydro-b-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to a4b2 nAChRs. Conclusions: The present results suggest that allosteric modulation of a4b2 nAChR may provide new strategies in chronic neuropathic pain. Significance: a4b2 nAChRs are involved in pain modulation. dFBr, a PAM at a4b2 nAChRs, potentiates the nicotine response dosedependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of a4b2* nAChR may provide new strategies in chronic neuropathic pain.

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Nicotinic Acetylcholine Receptor Modulators

Mazurov¹,

Yohannes

2014

Small Molecule Therapeutics for Schizophrenia

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Nicotine and its pharmacology have long been associated with schizophrenia and its epidemiology and treatment. Schizophrenics use nicotine in its major delivery form of cigarettes at a significantly higher incidence than the general population (80-90% vs. 25-30% of the general population) and even than those diagnosed with other psychiatric diseases. Various studies have demonstrated that cigarette smoking transiently restores cognitive and sensory deficits in patients with schizophrenia/schizoaffective disorders. Conversely, smoking cessation appears to exacerbate the symptoms of the disease. A disturbance of nicotinic receptor expression, affecting the α7 and α4β2 subunits, in various cerebral areas has been revealed in postmortem binding studies. Genetic linkage studies have also demonstrated that the α7 subunit is involved in the pathology of schizophrenia. Much of the drug discovery and development efforts in the nAChR field have focused on α7 and α4β2 nAChR subtypes. These include studies using nicotine and varenicline (the smoking cessation drug marketed as Chantix or Champix) as well as numerous other small-molecule therapeutics targeting these receptor subtypes. While some early studies included α4β2 modulators, the large majority of drug development of nAChR ligands for schizophrenia have been α7 agonists and partial agonists. Such therapeutics are in late-stage development and may constitute a breakthrough for the treatment of schizophrenia with safe and effective medicines.

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Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4β2 nAChRs

Cited by 21 publications

References 51 publications

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain

Nicotinic Acetylcholine Receptor Modulators

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