Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats

Mohler, Eric G.; Franklin, Stanley R.; Rueter, Lynne E.

doi:10.1007/s00213-013-3207-5

Cited by 19 publications

(18 citation statements)

References 41 publications

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“…Importantly, the adverse autonomic side effects associated with ABT-594 were not enhanced by NS9283 suggesting that PAM-based approaches may widen the therapeutic window of other therapeutic compounds. A similar lack of “stand-alone” effect of NS9283 was also observed in the auditory discrimination task [134] and in the nicotine drug discrimination task in rats [135]. In the nicotine drug discrimination task, NS9283, but not ABT-594, failed to generalize to the interoceptive nicotine cue.…”

Section: Nachr Positive Allosteric Modulators-role As Standalone Asupporting

confidence: 55%

“…In the nicotine drug discrimination task, NS9283, but not ABT-594, failed to generalize to the interoceptive nicotine cue. However, co-administering a fixed low dose of either nicotine or ABT-594 with increasing doses of NS9283 resulted in a complete substitution for the nicotine discriminative stimulus [135]. Overall, the findings with NS9283 point to discrete differences in endogenous cholinergic levels within neural substrates responsible for mediating specific neurobiological activities (e.g., cognition vs. pain) and thus, regional cholinergic tone dictates whether the nAChR PAM will activate the nAChR channel directly (“stand-alone”) or require the presence of an exogenous agonist (“adjunctive or promoter”) to produce the neurobiological response.…”

Section: Nachr Positive Allosteric Modulators-role As Standalone Amentioning

confidence: 99%

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Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Terry

Callahan

Hernandez

2015

Biochemical Pharmacology

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The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer’s disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of “multitarget-directed ligands” (MTDLs), the development and/or identification of compounds that exhibit “multifunctional” activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), “repurposing” strategies for existing compounds that have other clinical indications, and novel “adjunctive” treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, “multifunctional” properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and affinity α7 nAChR.

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Section: Nachr Positive Allosteric Modulators-role As Standalone Asupporting

confidence: 55%

Section: Nachr Positive Allosteric Modulators-role As Standalone Amentioning

confidence: 99%

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Terry

Callahan

Hernandez

2015

Biochemical Pharmacology

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“…It is worth noting that PNU-120596 alone, at the dose used, did not induce changes in locomotor activity (Supplementary Figure S5b), nor did it show pro-depressant activity in the forced swim test (Supplementary Figure S6). In contrast, a systemic injection before SubSD of NS9283, a β2*nAChR-selective positive allosteric modulator, 33 did not induce social avoidance behavior (Supplementary Figure S7). This demonstrates a specific role of α7* nAChRs in the expression of social avoidance induced by social stress.…”

Section: Stress and Nicotine Detrimental Interplay C Morel Et Almentioning

confidence: 94%

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

et al. 2017

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Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking β2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

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“…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 allow an increased therapeutic index for compounds inducing adverse effects. Finally, NS9283 has also been investigated in a drug discrimination paradigm, in which the compound increased the discriminative stimulus effect of low-dose nicotine and the a4b2-preferring agonist ABT-594 [86]. With regard to basal physiological parameters, NS9283 does not affect neither locomotor activity, rectal temperature nor cardiovascular parameters [15,83].…”

Section: A4b2 Nachr Pamsmentioning

confidence: 99%

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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Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats

Cited by 19 publications

References 41 publications

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

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

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