Therapeutic Targeting of the α7 Nicotinic Receptor: Challenges and Prospects for Cognitive Improvement in Alzheimer's and Schizophrenia

ABSTRACT

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a key target for treating cognitive dysfunction in neurological disorders such as Alzheimer's disease (ad) and schizophrenia. α7 nAChRs play essential roles in neurotransmission, neuroinflammation and synaptic plasticity, not only in neurons but also in glial cells, where they engage in metabotropic signalling. Despite promising preclinical findings, clinical trials of α7 nAChR agonists, partial agonists and positive allosteric modulators (PAMs) have yielded inconsistent results, with few achieving sustained cognitive benefits in patients. This review examines the functional properties of α7 nAChRs, ionotropic and metabotropic signalling roles, and their contribution to cognitive processes in ad and schizophrenia. We provide a comprehensive analysis of key α7‐targeted compounds that advanced to clinical trials, detailing their outcomes and challenges. Additionally, we discuss major translational barriers, including receptor desensitization, pharmacokinetic limitations, inter‐individual variability (e.g., effects of smoking on metabolism) and species differences in preclinical models. Finally, we explore innovative strategies to improve trial success, including optimized dosing regimens, co‐administration with PAMs and neuroimaging techniques like PET to refine patient selection and drug evaluation. These approaches may offer a more effective pathway for developing α7‐targeted cognitive therapies in ad and schizophrenia.

Summary.

The α7 nicotinic acetylcholine receptor (α7 nAChR) plays a crucial role in brain functions related to memory and thinking. This review looks at how drugs designed to stimulate these receptors may help treat cognitive issues in Alzheimer's disease and schizophrenia. Over the years, many drugs have been developed and tested in clinical trials, but most have failed to show lasting improvements in memory or thinking skills. The review discusses possible reasons for these failures and explores new strategies, such as better trial designs and combination therapies, which could improve future treatments targeting these receptors.

1. Introduction

The discovery of acetylcholine as a neurotransmitter revolutionized our understanding of how nerve cells communicate, leading to the identification of nicotinic acetylcholine receptors (nAChRs), members of the Cys‐loop ligand‐gated ion channel superfamily [1]. These receptors, composed of five subunits, form a central ion channel that opens upon acetylcholine binding, allowing ion flow and membrane depolarization. nAChRs are classified into three groups based on their subunit composition:

1. muscle‐type subunits (α1, β1, δ, ε, γ),

2. heteromeric neuronal αβ subunits (α2‐α6, α10, β2‐β4), and

3. homomeric neuronal subunits (α7‐α9).

Among neuronal nAChRs, the most widely expressed subtypes in the CNS are heteromeric α4β2 receptors and homomeric α7 receptors [2], while α3β4 is the dominant subtype in the PNS [3]. These receptors vary in subunit stoichiometry, leading to different functional and pharmacological properties. For instance, α4β2 nAChRs exist in two stoichiometries: the (α4β2)₂α4 configuration, which has an additional ligand‐binding site at the α4/α4 interface, and the (α4β2)₂β2 configuration, which exhibits a higher affinity for acetylcholine. The arrangement of the five subunits plays a crucial role in regulating the channel's kinetics, ion conductance and selectivity, while also influencing the pharmacological properties of the ligand binding sites and the channel's preference for specific cations [4]. In heteromeric α4β2 nAChR, acetylcholine (ACh) binds to a primary site at the α4/β2 interface, with both subunits contributing to its pharmacology. In contrast, homomeric α7 receptors contain five identical ligand‐binding sites, positioned between adjacent α7 subunits, leading to distinct kinetic and desensitization properties [5] (Figure 1).

FIGURE 1.

The organization and structure of nAChRs can be either heteropentameric or homopentameric. Both subtypes have distinct ACh‐binding sites. The heteropentameric α4β2 and α6β2β3 receptors, which are predominant in the CNS, have two identical binding sites (small blue circle) located between α4/α6 and β2 subunits, respectively, while the heteropentameric α6α4β2β3 subtype has two different binding sites at the interfaces of α4β2 and α6β2. The α3β4 receptor, which is predominant in the peripheral nervous system (PNS), particularly in autonomic ganglia, also follows a heteropentameric organization and plays a key role in peripheral neurotransmission. The homomeric α7 subtype features five ACh‐binding sites.

The endogenous neurotransmitter ACh, along with exogenous agonists like nicotine, binds at the orthosteric binding site located in the extracellular domain of the receptor, positioned between two subunits [6]. In addition, there are allosteric modulatory sites on the nAChR where positive allosteric modulators (PAMs) bind and enhance receptor function. PAMs facilitate agonist binding by inducing conformational changes, lowering the energy barrier for transitioning from a closed to an open state, or stabilizing the open state, thus modulating receptor activity [7].

2. Function and Distribution of the Neuronal Nicotinic Acetylcholine Receptor

All neuronal nAChR subtypes share the key feature of being permeable to small monovalent and divalent cations, primarily sodium, potassium and calcium. Upon agonist binding, the receptor undergoes a tertiary conformational change, stabilizing the channel in its open state and allowing cation flow. The channel then either returns to its resting state or transitions into a desensitized state, where it becomes unresponsive to further activation (Figure 2).

FIGURE 2.

The α7 nAChR exists in three main functional states: resting, active and desensitized. In the resting state, the channel is closed, and no ionotropic or metabotropic signalling occurs. When a ligand such as acetylcholine (ACh, yellow ball) binds, the receptor transitions to the active state, where the channel opens, permitting ion flow (ionotropic signalling), and metabotropic signalling pathways may also be engaged. In the desensitized state, prolonged ligand binding keeps the channel closed, preventing ionotropic signalling while still allowing metabotropic activity through intracellular signalling cascades.

At the synaptic cleft, brief exposure to high concentrations of an agonist causes a synchronous opening of nAChR pores, while prolonged exposure leads to partial activation and significant desensitization, resulting in the receptors entering a closed, unresponsive state [8]. This mechanism is crucial in assessing the therapeutic potential of the receptor, as extended use of an α7 nAChR agonist may not sustain receptor activation. Therefore, it is important in clinical settings to consider the effects of prolonged and repeated exposure to prevent tachyphylaxis.

In addition to their well‐characterized ionotropic function in neurons, where α7 nAChRs mediate fast excitatory signalling through calcium influx, these receptors can also engage in metabotropic signalling in glial cells such as microglia and astrocytes [9]. Through interactions with intracellular G‐proteins, glial α7 nAChRs activate distinct downstream signalling pathways, which may have functional implications for neuroinflammation and synaptic modulation [10]. This dual signalling capacity suggests that α7‐targeted therapies may differentially impact neuronal and glial populations, influencing cognitive function in both Alzheimer's disease (ad) and schizophrenia, though the specific contributions of ionotropic and metabotropic signalling to cognitive improvement remain unclear across different cell types and disease contexts.

In the brain, α7 nAChRs are highly expressed in areas linked to cognitive and sensory functions, memory and attention. Key regions include the hippocampus, cerebral cortex, thalamus and amygdala [5]. The hippocampus, especially in the CA1, CA3 and dentate gyrus areas, has a dense concentration of α7 nAChRs, which play a crucial role in learning, memory and synaptic plasticity [11]. Additionally, the cerebral cortex, particularly layers I and VI, which are involved in higher cognitive functions, has significant expression of α7 nAChRs [12]. Apart from their presence in regions associated with higher cognitive functions, α7 nAChRs are also found in sensory processing areas. In the thalamus, α7 nAChRs modulate synaptic transmission and contribute to sensory gating processes [1]. Similarly, α7 nAChRs are expressed in the amygdala potentially playing a role in emotional regulation and fear conditioning [13]. Finally, the presence of α7 nAChRs in the substantia nigra and ventral tegmental area highlights their involvement in modulating the dopaminergic system and reward processing [14].

3. Nicotinic Receptor's Role in Memory and Cognition

The hippocampus is essential for learning, cognition and the processes of memory formation, consolidation and retrieval. Additionally, spatial navigation and the development of cognitive maps are heavily reliant on proper hippocampal function, where nAChRs are densely distributed throughout all layers. The α7 nAChRs are primarily found in the granule and pyramidal cells of the hippocampus [15]. Activation of α7 nAChRs affects neural networks through several mechanisms. First, it directly depolarizes neurons, especially interneurons, due to the high expression of α7 receptors in their somatic regions [16]. Second, α7 nAChR activation modulates both glutamatergic and GABAergic transmission through pre‐ and postsynaptic mechanisms. Third, the timing of α7 nAChR activation relative to glutamatergic transmission plays a crucial role in regulating synaptic plasticity [17]. For instance, activation of α7 nAChRs increases the presynaptic release of both glutamate and GABA, promoting the induction of long‐term potentiation (LTP). However, the specific effects on primary excitatory cells depend on the location and timing of receptor activation. For example, in CA1 interneurons, α7 nAChR activation may suppress the induction of short‐term potentiation in connected pyramidal neurons, whereas activation on CA1 dendrites in pyramidal neurons can enhance short‐term potentiation (STP) or LTP [18]. These diverse effects highlight the complex regulatory role of α7 nAChRs in hippocampal synaptic plasticity, ultimately influencing learning, memory formation and cognition [19]. Studies in both animal models and humans suggest that external activation of α7 nAChRs enhances synaptic plasticity, facilitates LTP and improves memory formation, while receptor antagonists are associated with impaired cognitive function [20].

While neurons have been traditionally viewed as the central mediators of cognition, increasing evidence suggest the role of glial cells in modulating synaptic plasticity, learning and memory [21]. Astrocytes regulate synaptic transmission by buffering extracellular ions, releasing neuromodulators and modulating local blood flow, thereby influencing neuronal excitability and network dynamics. Their ability to couple multiple synapses into functional assemblies suggests they may contribute to higher‐order information processing, including memory consolidation and network oscillations [22]. Microglia actively prune synapses in an activity‐dependent manner, refining neural circuits to optimize cognitive function. However, dysregulated microglial activation can lead to neuroinflammation and impair synaptic plasticity, contributing to cognitive deficits in neurodegenerative and psychiatric disorders [23]. α7 nAChRs are highly expressed on microglia, where their activation has been shown to suppress pro‐inflammatory cytokine release and regulate synaptic remodelling, linking cholinergic signalling to neuroimmune modulation [24]. Similarly, oligodendrocytes contribute to cognition by modulating conduction velocity through myelination, affecting spike timing, oscillatory activity and synchrony in neuronal networks [25]. Given the role of α7 nAChRs in regulating neuroinflammatory pathways, targeting α7 receptors in glial cells may influence cognitive function not only through neuronal effects but also by modulating glial responses. These mechanisms highlight how α7‐targeted therapies could have broader implications for cognitive improvement in ad and schizophrenia by affecting both neuronal and non‐neuronal cell populations.

4. The Role of the α7 Nicotinic Receptor in Alzheimer's Disease

ad is a complex neurodegenerative disorder characterized by cognitive decline, memory impairment and synaptic dysfunction and is the leading cause of dementia in older adults, with significant impacts on patients, families and economic burden [26]. The α7 nAChR has received significant attention in ad research due to its role in disease pathogenesis. Found on neurons and glial cells, these receptors are involved in neuroprotective signalling pathways and may contribute to neuroprotection in ad and their activation can release neurotrophic factors such as brain‐derived neurotrophic factor, which supports neuronal survival and plasticity [27]. Furthermore, α7 nAChRs possess anti‐inflammatory properties, regulating microglial activation and cytokine production to help protect against neuroinflammation in ad [28] as well as regulating inflammation by modulating cytokine release from macrophages [29]. They are also involved in the clearance of amyloid beta (Aβ), a critical process in ad. Microglial cells degrade Aβ, aiding in its removal and potentially slowing disease progression [30]. Aging can shift microglia into a pro‐inflammatory state, reducing their phagocytic function, but activating α7 nAChRs has been shown to reverse this shift and enhance microglial clearance and metabolism of Aβ [31].

These findings suggest that nicotine intake and cholinesterase inhibitors may reduce Aβ accumulation and improve ad symptoms. Studies in rat microglia [32] and transgenic mice [33, 34] showed positive effects from nicotine or cholinesterase inhibitors, while the knock‐out of α7 nAChR, or the use of antagonists or antibodies targeting the receptor, diminished these benefits or worsened pathology. However, in ad patients, cholinesterase inhibitors have shown only limited cognitive improvements, primarily in the early stages of the disease, and their effects are often restricted by cholinergic side effects [35]. Regarding nicotine and its effect on ad, the picture is less clear. A meta‐analysis showed that smoking increases the risk of cognitive impairment and ad in individuals aged 65–75, but not in those under 65 [36]. This age‐related difference could be explained by the interaction between Aβ and α7 nAChRs, although the exact consequences remain uncertain. The presence of the α7β2 isoform in basal forebrain cholinergic neurons complicates the ad pathology, as this receptor is sensitive to Aβ, leading to inhibition of ACh responses even at low concentrations [37]. The blockade of α7β2 receptors may promote a feedback loop where impaired Aβ clearance leads to neuronal degeneration and further neurotoxicity. Early intervention with nicotine, cholinesterase inhibitors and α7 nAChR agonists may help delay this loop, but in later ad stages, Aβ accumulation reduces α7 nAChR availability, possibly explaining the detrimental effects of smoking.

The role of α7 nAChRs in ad is complex, with both neuroprotective potential and contributions to disease progression. The cholinergic hypothesis, proposed over four decades ago, links cognitive deficits in ad to the loss of cholinergic neurons and reduced ACh release. This is supported by evidence of reduced nicotinic receptor binding sites in ad brains. While α4β2 nAChR levels consistently decrease in ad, findings on α7 nAChRs are more mixed, with reports of both increased and decreased receptor levels depending on the brain region and cell type examined. Further, variability in findings may stem from differences in sample size, disease stage and methodological approaches, such as immunohistochemical markers and PET imaging tracers used to quantify α7 expression. Post‐mortem studies suggest that α7 nAChRs are upregulated in reactive astrocytes but downregulated in neurons, particularly in the hippocampus and entorhinal cortex [38]. Moreover, the co‐localization of α7 nAChRs with amyloid plaques in some studies has led to speculation that astrocytic α7 upregulation may be a compensatory response to amyloid pathology rather than a primary disease driver [39].

5. α7 Nicotinic Receptors and Cognitive Dysfunction in Schizophrenia

Schizophrenia is a complex psychiatric disorder marked by positive symptoms like hallucinations and delusions, negative symptoms such as blunted affect and social withdrawal, and cognitive deficits affecting executive function, memory and processing speed [40]. Cognitive impairment is a core feature of schizophrenia, often emerging before psychotic symptoms and persisting throughout the illness, significantly impacting long‐term outcomes [41].

Antipsychotics are the primary treatment used for patients with schizophrenia and are effective in reducing positive symptoms in some but do not consistently improve cognitive function, leaving an unmet need [42]. Despite decades of drug discovery efforts, no pro‐cognitive compounds have been approved [43]. The challenge lies in the complex aetiology of schizophrenia, which involves multiple neurotransmitter systems, including dopaminergic, serotonergic, glutamatergic, adrenergic and cholinergic pathways.

Over the past two decades, growing interest in the role of the α7 nAChR in the cognitive deficits of schizophrenia has provided insights into disease mechanisms and potential treatments, supported by behavioural, neurobiological and genetic evidence [44]. Firstly, individuals with schizophrenia have a much higher prevalence of tobacco use (70–85%) compared to the general population (~20%), and they tend to extract more nicotine and smoke more cigarettes per day [45]. This increased nicotine consumption is thought to be a form of self‐medication for cognitive symptoms [46]. Secondly, post‐mortem studies of brains from individuals with schizophrenia have revealed a reduction in α7 nAChR expression and function, particularly in brain regions associated with cognitive processing and sensory gating [47]. Finally, genetic research has identified single‐nucleotide polymorphisms in the CHRNA7 gene, which encodes α7 nAChR subunits, as being linked to an increased risk of schizophrenia [48].

Beyond their role in neurotransmission and previously described involvement in glial function, α7 nAChRs may also contribute to schizophrenia pathophysiology through their effects on glial cells. Glial cell loss is a key feature of schizophrenia histopathology, with deficits in oligodendrocytes, astrocytes and microglia contributing to impaired synaptic connectivity, neurotransmitter regulation and neuroimmune responses [49]. Dysregulated α7 signalling may impair microglial homeostasis, leading to excessive synaptic pruning and the connectivity deficits observed in schizophrenia. Similarly, oligodendrocytes express α7 nAChRs, and their function in cholinergic modulation of myelination suggests that α7 dysfunction could contribute to the myelination deficits reported in schizophrenia. Finally, astrocytes rely on α7 signalling to regulate glutamate uptake and extracellular homeostasis, and impaired receptor function may lead to glutamate dysregulation, excitotoxicity and neuronal instability. These findings suggest that dysfunction of α7 nAChRs in glial populations may play a role in the pathophysiology of schizophrenia and that targeting these receptors in glial cells could represent an alternative strategy for cognitive enhancement beyond direct neuronal effects.

6. Therapeutic Targeting of α7 nAChRs in ad and Schizophrenia

Although ad and schizophrenia have distinct pathological mechanisms, both involve cognitive deficits linked to α7 nAChR dysfunction, making the receptor a therapeutic target in both conditions [50, 51] (Table 1). In ad, α7 activation is associated with neuroprotection, amyloid clearance and cholinergic support, whereas in schizophrenia, α7 dysfunction contributes to sensory gating deficits and cognitive impairment. The high smoking prevalence in schizophrenia adds another layer of complexity, as chronic nicotine exposure may influence α7 receptor function and therapeutic response. These parallels and distinctions have driven sustained interest in α7‐targeted therapies across both conditions.

TABLE 1.

List of compounds developed targeting the α7 nAChR in ad and schizophrenia that progressed to clinical trials and reasons for their discontinuation. Type: (A) = agonist, (PA) = partial agonist, (PAM) = positive allosteric modulator. Table compiled from [50, 51], and available data on clinicaltrials.gov.

Name, (type)	Indication	Clinical phase at discontinuation	Result/reason discontinued	Clinicaltrials.gov identifier (NCT)	Reference
ABT‐126 (PA)	AD	2	Trend in cognitive performance improvements	00948909	Gault et al., 2015
ABT‐126 (PA)	AD	2	No significant effects	01527916	Florian et al., 2016
ABT‐126 (PA)	Schizophrenia	2	No significant effects	01678755	Haig et al. 2016
AQW051 (PA)	Mild cognitive impairment	2	Terminated; unknown reason	00582855	None found
AQW051 (PA)	Schizophrenia	2	None reported	01730768	Barch et al., 2016
AQW051 (PA)	L‐DOPA‐induced dyskinesia	2	No significant effects	01474421	Trenkwalder et al., 2016
AVL‐3288 (PAM)	First‐in‐human	1	Trend on cognitive improvement	01851603	Gee et al., 2017
AVL‐3288 (PAM)	Schizophrenia	1	No significant effects	02978599	Kantrowitz et al., 2020
AZD0328 (PA)	PK study	1	Company decision	00687141	Sydserff et al., 2009
AZD0328 (PA)	Schizophrenia	2	Company decision	00669903	Sydserff et al., 2009
EVP‐6124 (PA)	Schizophrenia	1	Positive effects in performance on cognitive tests	01556763	Preskorn et al., 2014
EVP‐6124 (PA)	Schizophrenia	2	Cognitive improvements	00968851	Keefe et al., 2015
EVP‐6124 (PA)	AD	2	Cognitive improvements	01073228	Deardorff et al., 2015
EVP‐6124 (PA)	ad	3	Clinical hold due to adverse events	01969123, 01969136	None found
EVP‐6124 (PA)	Schizophrenia	3	No significant effects	01714661, 01716975	Brannan, 2019
GTS‐21 (PA)	Probable AD	2	No significant effects	00414622	Kem, 2000
GTS‐21 (PA)	Schizophrenia	2	No significant effects	01400477, 00100165	Freedman et al., 2008
JNJ‐39393406 (PAM)	Smoking cessation in patients with schizophrenia	2	No treatment benefit	02230384	Perkins et al., 2018
JNJ‐39393406 (PAM)	Cognition in patients with unipolar depression	2	No treatment benefit	02677207	Davidson et al., 2021
JNJ‐39393406 (PAM)	Schizophrenia	1	No treatment benefit	01137799	Winterer et al., 2013
RG3487 (PA)	AD	2	Not reported	00884507	None found
RG3487 (PA)	Schizophrenia	2	No cognitive improvement	00604760	Umbricht et al., 2014
SSR18071 (PA)	Mild AD	2	Early terminated	00602680	Biton et al., 2007
TC‐5619 (A)	PK in healthy elderly and AD	1	Not reported	01254448	Mazurov et al., 2012
TC‐5619 (A)	Schizophrenia	2	Cognitive improvements	01003379	Lieberman et al., 2013
TC‐5619 (A)	ADHD	2	Not reported	01472991	None found
TC‐5619 (A)	Schizophrenia	2	No significant effects	01488929	Walling et al., 2016

Among the numerous compounds tested, encenicline (EVP‐6124) advanced the furthest in clinical development. Early trials in schizophrenia patients yielded promising cognitive improvements [52], and a phase 2, placebo‐controlled trial in patients with mild‐to‐moderate ad also demonstrated significant enhancements in both cognitive and functional outcomes [53]. Similarly, a phase 2 placebo‐controlled trial in participants with schizophrenia showed significant and clinically meaningful improvements in cognition [54]. Despite these encouraging results, the compound faced setbacks. In 2015, two large phase 3 trials in ad were suspended due to gastrointestinal side effects [55], and later phase 3 trials in schizophrenia failed to meet their primary endpoints (Brannan, 2019), halting further development of the compound for both conditions [56].

Beyond encenicline, several other partial agonists have been developed and tested at various stages, but none have succeeded in delivering consistent cognitive benefits across both ad and schizophrenia. GTS‐21 (also known as DMXB‐A), one of the earliest tested α7 nAChR agonists, improved cognitive performance in healthy volunteers [57], but when tested in ad patients, no significant treatment benefits were observed [58]. Interestingly, GTS‐21 did show promise in alleviating negative symptoms in schizophrenia in a separate phase 2 study [59]. Another partial agonist, SSR180711, was evaluated in a 4‐week, placebo‐controlled phase 2 trial in patients with mild ad, but the trial was terminated early due to an unfavourable risk–benefit ratio, and the results remain unpublished. AZD0328 was found to improve operant responding acquisition and novel object recognition in mice [60], but failed to meet the primary endpoints in a phase 2 trial with schizophrenia patients (results not published). A small pharmacokinetic study in healthy elderly participants represented the extent of AZD0328's evaluation in ad. Similarly, ABT‐126 showed a modest trend toward cognitive improvement in a 12‐week phase 2 clinical trial in patients with mild‐to‐moderate ad [61], but a subsequent larger trial with 438 patients failed to confirm these results [62, 63]. ABT‐126 also showed no significant cognitive improvement in patients with schizophrenia [64]. RG3487 delivered positive outcomes in a phase 2 study involving 80 patients with mild‐to‐moderate ad [65], but a larger, 6‐month placebo‐controlled trial with 389 ad patients was inconclusive, and the results were never fully published. The compound also failed to improve cognition in a phase 2 trial with patients with schizophrenia [66]. AQW051, another partial agonist, was tested in both ad and schizophrenia, but trials yielded inconclusive results, and the compound was eventually discontinued [67]. AQW051 also did not show efficacy in treating L‐Dopa‐induced dyskinesia in Parkinson's patients [68].

While many partial agonists that have been evaluated, only one full agonist, bradanicline (TC‐5619), has undergone clinical testing [69]. Results from a 12‐week, placebo‐controlled phase 2 trial involving 184 patients with schizophrenia were encouraging, showing significant cognitive improvements [70]. However, later trials in schizophrenia failed to meet efficacy endpoints, leading to the discontinuation of bradanicline's development. In a phase 2 trial for schizophrenia, bradanicline (TC‐5619) did not demonstrate statistically significant improvements over placebo on primary or secondary outcome measures, including negative and cognitive symptoms [71]. Specifically, there was no significant difference between bradanicline and placebo in the Scale for the Assessment of Negative Symptoms (SANS) composite score, nor in secondary measures such as the Cogstate Schizophrenia Battery (CSB), University of California San Diego Performance‐Based Skills Assessment (UPSA‐B), Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression scales (CGI‐I and CGI‐S). While post hoc analyses suggested a potential benefit in tobacco users, these findings were inconsistent across doses, countries and cognitive assessments [71]. Several factors may have contributed to the lack of efficacy in this trial. Unlike the earlier exploratory study, which used a titration approach (1–25 mg), this study used fixed doses (5 mg and 50 mg), which may have affected receptor activation or desensitization. Additionally, differences in study populations, placebo response rates and permitted antipsychotic co‐treatments could have played a role in the observed discrepancies. Given these results, further development of bradanicline for schizophrenia was discontinued. While this compound was also explored for adHD and ad, the outcomes of those trials have not been reported.

An alternative approach to targeting α7 nAChRs has involved PAMs, which enhance receptor function without directly activating the receptor. This modulation is particularly relevant given the distinct functional states of α7 nAChRs. PAMs can counteract the receptor's tendency toward rapid desensitization by stabilizing active conformations, thereby prolonging ionotropic signalling. However, α7 nAChRs also engage in metabotropic signalling, particularly in glial cells, where non‐conducting receptor states can activate intracellular pathways. In immune cells and microglia, α7 activation can regulate JAK2/STAT3 modulating inflammatory responses independent of ion flux [72]. This suggests that α7‐targeted therapies may differentially affect neuronal and glial populations, with PAMs favouring ionotropic neurotransmission in neurons, while certain agonists or silent agonists may preferentially enhance metabotropic effects in non‐neuronal cells.

This method allows for more refined modulation of receptor activity, making PAMs a promising therapeutic option [73]. Two PAMs, AVL‐3288 and JNJ‐39393406, have advanced to clinical trials. AVL‐3288 showed potential cognitive benefits in a phase 1 trial involving healthy participants [74], but subsequent trials in schizophrenia did not yield improvements [75]. JNJ‐39393406 was tested in clinical trials for smoking cessation and for treating cognitive or depressive symptoms in patients with unipolar depression, but none of the trials met their endpoints [76]. A phase 1 study in schizophrenia also showed no improvement in sensory gating deficits, and the drug's development was discontinued [77, 78]. Additionally, galantamine, an FDA‐approved acetylcholinesterase inhibitor for ad, has been suggested to function as a PAM of α7 nAChRs [79], though this has been debated [80]. Regardless, its potential dual mechanism, cholinergic potentiation via acetylcholinesterase inhibition and potential α7 modulation, has been linked to cognitive benefits in ad, although these effects are considered moderate [81]. In schizophrenia, trials on galantamine's cognitive effects have shown mixed results. A meta‐analysis found a small but significant improvement [82], while a 12‐week randomized trial reported selective benefits in processing speed and verbal memory but no overall cognitive enhancement [83]. These findings suggest modest and inconsistent effects, with potential for greater impact in combination therapies.

Antagonists of α7 nAChR are less impactful than agonists, partial agonists and PAMs. Memantine, primarily an NMDA receptor antagonist, also acts as an α7 nAChR antagonist, though its benefit in ad is unclear [84]. Other antagonists include conotoxins, which selectively and reversibly target α7 nAChRs, and α‐Btx, which binds irreversibly. Due to their inability to cross the blood–brain barrier, both primarily act in the peripheral nervous system, limiting their practical use.

Despite the challenges in α7‐targeted drug development, its involvement in neuroprotection, synaptic plasticity and cognitive processing continues to make it an attractive therapeutic target in both ad and schizophrenia. Future strategies may need to consider combination therapies or address disease‐specific factors, such as receptor desensitization in schizophrenia, to optimize therapeutic outcomes. However, the failure of multiple α7‐targeted compounds in late‐stage clinical trials suggests that therapeutic potential alone is not sufficient; key obstacles remain in translating preclinical success into clinical efficacy. Understanding why these promising strategies have not yielded consistent benefits requires a closer examination of the limitations in current drug development approaches.

7. Translational Challenges in α7 nAChR Drug Development

The disappointing results of clinical trials for pro‐cognitive drugs targeting α7 nAChRs in schizophrenia and ad raise concerns about the translational validity of animal models. A major challenge in drug discovery for these disorders is the subjective nature of symptoms, lack of reliable biomarkers and objective diagnostic tests, and limited understanding of their neurobiology and pathophysiology [85]. Rodent models are crucial in basic research and early testing of therapeutic agents, but overreliance on them in later preclinical stages of neuropsychiatric and neurological drug development can be problematic. The reliance on rodent models is questionable due to their limited behavioural repertoire and significant anatomical differences, especially in cortical regions involved in cognition. Genetic and pharmacological differences in α7 nAChRs between rodents and humans may also contribute to inconsistent outcomes between preclinical and clinical trials. For instance, while humans with 15q13.3 microdeletion syndrome show schizophrenia‐like behaviours, a knockout mouse model of the same gene did not exhibit this phenotype [86].

PK studies show further differences between rodent and human α7 nAChRs: in vitro, GTS‐21 stimulates the rat receptor at more than double the response of the human receptor, and the inhibition constant (K _i) is about 10 times lower in rats, indicating that similar serum levels may have different effects across species [87]. Furthermore, although the general organization of brain structures is similar between rodents and humans, a study by Hodge, Bakken [88] highlights significant differences in gene expression among comparable cell types in mouse and human brains. These differences could play a crucial role in explaining the limited success of translating pharmacological treatments for CNS disorders between rodents and humans. Despite advances in tissue models like brain organoids and in silico systems, animal models remain essential. However, there is a need for species that more closely resemble humans in behaviour and brain anatomy for neuropsychiatry and drug discovery research.

8. Clinical Trial Design and Dosing Strategies

Another limitation to the clinical studies is linked to decisions regarding dosage, administration frequency and treatment duration. Unlike animal studies that frequently show robust cognitive effects with acute or subacute dosing of α7 nAChR ligands [89], many clinical trials have used much longer durations. Prolonged exposure to an agonist leads to temporary inactivity in α7 nAChRs as described earlier, potentially resulting in receptor desensitization or even functional antagonism [90]. Studies have shown that α7 nAChR ligands are more effective at lower concentrations, with higher doses leading to receptor desensitization and producing an inverted‐U shaped dose–response curve [44]. As an example, a study in non‐human primates demonstrated that low doses of PHA543613, an α7 nAChR agonist, improved cognitive performance and enhanced neuronal activity in the prefrontal cortex, but treatment with higher doses were ineffective [91]. Also, the investigators of the TC‐5619 phase 2 clinical trial suggested that the chosen dosing strategy and treatment duration may have influenced the primary outcome. They speculated that lower doses might be enough to trigger CNS processes leading to clinical benefits, while higher doses or extended treatment could desensitize or fail to activate these processes [71].

Beyond dosing strategies, pharmacokinetic factors further influence α7 nAChR‐targeted drug efficacy, particularly in relation to metabolism, receptor desensitization and inter‐individual variability. Studies with different formulations of DMXB‐A highlight key challenges, including its short plasma half‐life (~60 min), which results in transient receptor activation, while longer‐acting formulations fail to improve cognitive outcomes, likely due to receptor desensitization [92]. Additionally, smokers exhibited 10‐fold lower plasma levels of DMXB‐A compared to non‐smokers, suggesting that chronic nicotine exposure accelerates hepatic metabolism via cytochrome P450 enzymes, reducing drug efficacy [92]. These findings suggest that future α7‐targeted therapies may require short‐acting agonists, intermittent dosing strategies or PAM coadministration to minimize desensitization and optimize receptor engagement. This approach could enhance receptor activation while allowing for lower doses and potentially reducing side effects, though it has not yet been tested in clinical trials. Additionally, using non‐invasive neuroimaging methods like PET in both preclinical and clinical studies could improve the selection of optimal doses for α7 nAChR ligands and enhance target engagement. Recent animal PET studies with TC‐5619 and encenicline revealed significant differences in receptor occupancy, with encenicline showing poor target engagement [93]. While a detailed discussion of PET imaging for α7 nAChRs is beyond the scope of this review, a separate publication provides an in‐depth analysis of PET radioligands, occupancy studies and dose selection strategies, expanding on the imaging‐based approaches for optimizing α7‐targeted therapies [94].

9. Conclusion

Early preclinical findings and initial clinical trials generated significant optimism, positioning the α7 nAChR as a promising target for cognitive therapy. However, as more compounds progressed through clinical development, the limitations of existing strategies became evident.

Despite its well‐established role in neurotransmission, α7 nAChR function extends beyond neurons, engaging in metabotropic signalling in glial cells that may influence cognitive outcomes. The receptor's involvement in neuroprotection, synaptic plasticity and neuroinflammation suggests a broader therapeutic potential than initially anticipated.

However, clinical results have repeatedly failed to match preclinical promise due to challenges such as receptor desensitization, poor pharmacokinetics (e.g., short half‐life, metabolism variability in smokers) and limitations in translational models. While early‐stage trials showed some promise, particularly with partial agonists and PAMs, the failure to achieve sustained cognitive improvement in large‐scale clinical studies underscores the need for innovative approaches. Future approaches should prioritize combination strategies, such as co‐administration of agonists with PAMs to prevent receptor desensitization and employ neuroimaging techniques like PET to refine patient selection, dosing strategies and biomarker‐based treatment validation. A deeper understanding of α7 nAChR dynamics, including its metabotropic functions and role in glial regulation, will be critical in advancing the development of pro‐cognitive therapies for these challenging neurological conditions.

Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.