Positive allosteric modulation of α4β2 nAChR agonist induced behaviour

Rode, Frederik; Munro, Gordon; Holst, Dorte; Nielsen, Elsebet Ø.; Troelsen, K.B.; Timmermann, Daniel B.; Rønn, Lars Christian B.; Grunnet, Morten

doi:10.1016/j.brainres.2012.03.064

Cited by 40 publications

(40 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with the PAM nature of NS9283, it was in the same study demonstrated that NS9283 by itself did not evoke any detectable current. In contrast to LY-2087101 in VTA, NS9283 did not potentiate nicotine-evoked a4b2-dependent dopamine release from striatal minces [53]. However, another study has suggested that striatal a4b2 nAChRs involved in dopamine release are of the HS stoichiometry [42], which would explain the inactivity of NS9283.…”

Section: Modulatory Actions Of A4b2 Pams On Neurotransmissionmentioning

confidence: 69%

“…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]. These studies also assessed whether NS9283 would exacerbate adverse effects of nAChR agonists used as analgesics.…”

Section: A4b2 Nachr Pamsmentioning

confidence: 94%

“…Although such investigations only provide indirect measures and not unequivocal proofs, a number of studies have indicated that both stoichiometries are expressed in vivo, suggesting that the existence of two stoichiometries is not just an experimental in vitro phenomenon. Both LS and HS receptors have been proposed to mediate glutamate release in mPFC ( [51] and [52], respectively), whereas only HS receptors so far have been suggested to mediate dopamine release in striatum [42,53]. Both stoichiometries may contribute to neurotransmission in Renshaw cells in mouse spinal cord [54].…”

Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriesmentioning

confidence: 99%

“…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%

“…The latter will modestly raise ACh levels and thereby compensate for the lowered cholinergic tone in neurodegenerative diseases, for example AD, and the PAM will by virtue of its nAChR subtype selectivity direct the effect of ACh primarily towards the desired receptor. 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%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

Section: Modulatory Actions Of A4b2 Pams On Neurotransmissionmentioning

confidence: 69%

Section: A4b2 Nachr Pamsmentioning

confidence: 94%

Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriesmentioning

confidence: 99%

Section: A4b2 Nachr Pamsmentioning

confidence: 99%

Section: Clinical Opportunities and Concerns With A4b2 Pamsmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors

Toma

Ulker

Alqasem

et al. 2020

Behavioral Pharmacology of the Cholinergic System

View full text Add to dashboard Cite

Positive allosteric modulation of α4β2 nAChR agonist induced behaviour

Cited by 40 publications

References 29 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

Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors

Contact Info

Product

Resources

About