Current Pharmaceutical Design - Volume 22, Issue 14, 2016

The frequency of neuropsychiatric disorders is greater than that of cancer, cardiovascular disease, and diabetes combined, and is growing at a faster rate than any other ailments in the United States or Europe. Despite a considerable need for the development of treatments for central nervous system disorders, pharmaceutical companies continue to reduce investment in this area of research. Of particular concern is the treatment of diseases and disorders that affect cognitive function, which are often given a lower priority for research investment than life threatening conditions or those with overt physical symptoms. Several reasons exist for this reduced investment, including a poor understanding of the mechanisms underlying impaired cognitive function, costly and long periods of development for these medications, disproportionately lower success rates, and a stigma associated with the medical treatment of mental illness. This paper will discuss these issues, review some of the successes resulting from research investment and discuss opportunities that should encourage increased research investment in cognitive disorders and their treatment.

Expressing functional nicotinic acetylcholine receptors (nAChRs) may be beneficial to central neurons and neuronal networks because activation of nAChRs enhances neuronal resistance to injury, improves attention, cognitive performance, and produces robust anti-inflammatory and analgesic effects in mammals. Although exogenous orthosteric nAChR ligands present valuable tools in treatment of age- and trauma-related neurological deficits, therapeutic approaches that could amplify the brain’s innate ability to maintain cholinergic homeostasis and resist injury may serve as intriguing and promising alternatives and have not been fully explored. One of these novel approaches utilizes positive allosteric modulators (PAMs) of nAChRs. Because of the ubiquitous expression of nAChRs in neuronal, glial and immune tissues, highly selective PAMs could amplify multiple endogenous neuroprotective, pro-cognitive, anti-inflammatory and anti-nociceptive cholinergic pathways to offset cholinergic hypofunction and generate therapeutic efficacy by targeting only a single player: i.e., nAChRs activated by endogenous cholinergic tone. In this article, I review the concept of allosteric modulation and current trends in therapeutic applications of nicotinic PAMs.

Alterations in gait and balance are manifest in numerous neurological disorders such as the ataxias and Parkinson's disease, and may occur as a consequence of stroke, traumatic brain injury and chemical insults to the brain. Although the underlying etiology of these disorders differs, disturbances in gait and balance appear to reflect deficits in cholinergic pathways within the brain. During the past 40 years, both clinical case studies and preclinical data have provided evidence that nicotinic cholinergic activation is beneficial for alleviating gait and balance deficits in many disorders. Further, studies indicate that activation of neuronal nicotinic receptors leads to neuroprotective and neurotrophic actions. And yet, despite these findings, there hsas been no concerted effort to develop neuronal nicotinic agonists for the treatment of abnormal gait and balance. The goal of this review is to shed light on the therapeutic benefit of the cholinergic nicotinic system for the treatment of ataxia, and discuss the challenges and limitations associated with developing drugs to treat disorders involving deficits in gait and balance.

The cholinergic activity in the brain is fundamental for cognitive functions. The modulatory activity of the neurotransmitter acetylcholine (ACh) is mediated by activating a variety of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Accumulating evidence indicates that both nAChR and mAChRs can modulate the release of several other neurotransmitters, modify the threshold of long-term plasticity, finally improving learning and memory processes. Importantly, the expression, distribution, and/or function of these systems are altered in several neurological diseases. The aim of this review is to discuss our current knowledge on cholinergic receptors and their regulating synaptic functions and neuronal network activities as well as their use as targets for the development of new and clinically useful cholinergic ligands. These new therapies involve the development of novel and more selective cholinergic agonists and allosteric modulators as well as selective cholinesterase inhibitors, which may improve cognitive and behavioral symptoms, and also provide neuroprotection in several brain diseases. The review will focus on two nAChR receptor subtypes found in the mammalian brain and the most commonly targeted in drug discovery programs for neuropsychiatric disorder, the ligands of α4β2 nAChR and α7 nAChRs.

Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer’s disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/β-catenin pathway, as well as β-amyloid. The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions, and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR function that are affected in AD.

Background: Alzheimer disease (AD) is a neurodegenerative disorder occurring in elderly people and leading to the loss of memory, practical and speaking habits. In spite of extensive efforts undertaken during the last decades, there is still no generally recognized explanation of the origin and primary pathological changes leading to AD development. Consequently, the suggested pharmacological approaches to treat the AD patients are mostly symptomatic and do not stop the disease progression. Neuroinflammation and cholinergic deficit usually accompany AD development. However, their impact in AD progression still waits for being properly recognized. Objective: The present review aims at analysis of the role of inflammation and nicotinic acetylcholine receptors, primarily of α7 subtype (α7 nAChRs), in the development of AD in humans and AD-like symptoms in experimental animals. Results: The reviewed data describe the involvement of α7 nAChRs in the AD pathogenesis, in particular, through their interaction with amyloid-β, maintenance of brain cell viability and regulation of neuroinflammation. They also delineate the role of α7-specific (auto)antibodies in stimulating neuroinflammation, memory impairment in mice and AD progression in humans. Conclusion: Neuroinflammation is suggested as a primary stimulus sufficient to trigger accumulation of pathologically processed amyloid-β, degeneration of cholinergic neurons and memory impairment. The level of α7 nAChR expression in the brain is critical for supporting the resistance to inflammatory and apoptogenic agents. The data presented may be a basis to create a new strategy for preventing and, possibly, slowing AD development in humans.

Background: Alzheimer’s disease (AD) is the most frequent progressive neurodegenerative disease. Cholinergic dysfunction is one of the major pathological alteration, although depletion of cholinergic neurons is caused by the well-established toxicity of the beta-amyloid plaques and neurofibrillary tangles. Cholinergic dysfunctions are consequences of the decrease in acetylcholine synthesis and release, and altered function of muscarinic and nicotinic cholinergic receptors. In addition, a direct correlation between cholinergic alteration, amyloidbeta production and tau phosphorylation, two main AD-pathology hallmarks, has been identified. Methods: In the present review we focused our discussion on the identification of new allosteric or bitopic ligands able to modulate the cholinergic receptor activity. Moreover drug delivery methodology (nanoparticeles, liposomes, etc.) that might contribute to drive the drug in the brain, reducing their toxicity and potential side effects have been also discussed. Results: Many drugs are currently in use for AD (e.g. donepezil, rivastigmine etc.) and several of those in development such as muscarininc and nicotinic agonists, target specifically the cholinergic system; the main mechanism aims to rescue the cholinergic dysfunction, to reduce neurotoxic protein accumulation and improve the cholinergic impairments responsible of the cognitive deficits. Promising approaches aim to either improve drug delivery into the brain or develope new compounds targeting known or new molecular pathways. Nanoparticles and liposomes are also described as new nanotechnology tools that overcome traditional routes of administration, with a particular focus on their employment for compounddelivery that targets the cholinergic system. Ultimately, a new fields of research is emerging as the use of induced pluripotent stem cells, a technology that allows to obtain cells directly from the patients that can be propagated indefinetely and differentiated into the susceptible neuronal subtypes. This may significantly contribute to improve the understanding of AD pathological processes and enhance current AD pharmacology beyond the cholinergic dysfunction. Conclusion: From the topics discussed in the present review, emerges that the combination between pharmacological studies and nanotechnological approaches for drug delivery and the identification of new specific models may largely enhance and improve the therapeutic strategies for different neurological disease including AD.

Nicotinic acetylcholine receptors are ligand-gated transmembrane ion channels that are present at the neuromuscular junction and in different locations in the nervous system. The different subtypes of neuronal nicotinic acetylcholine receptors that are found in the brain are thought to be involved in many neurological processes such as pain, cognitive function and depression, as well as in the pathophysiology of numerous neurological diseases and conditions. While the neurotransmitter acetylcholine is an endogenous agonist for all nicotinic receptors subtypes, many drugs that act as agonists and antagonists have also been identified or developed for these receptors. In addition, a novel class of compounds described as allosteric modulators have also been identified or developed for nicotinic acetylcholine receptors. Allosteric modulators are ligands that bind to nicotinic receptors at sites other than the orthosteric site where acetylcholine binds. One such allosteric modulator is desformylflustrabromine. Five chemical analogs along with desformylflustrabromine act as positive allosteric modulator for nAChRs that contain the beta2 subunit in their pentameric structure. Here the discovery and development, medicinal chemistry and pharmacological actions of desformylflustrabromine have been discussed. Desformylflustrabromine and its chemical analogs have the potential to develop into clinically used drugs for neurological diseases and conditions where nicotinic acetylcholine receptors are involved.

Background: Alzheimer’s disease is a neurodegenerative disease showing alterations in classical neurotransmitters, above all in the hippocampus and prefrontal/temporal cortices. In this disease, acetylcholine shows hypoactivity, noradrenaline first shows hyperactivity, and during the course of the disease an increasing hypoactivity, glutamate shows hyperactivity and excitotoxicity and GABA shows hypoactivity. In post-mortem studies, serotonin levels and the number of specific serotonergic subreceptors, for example 5-HT1B receptors, decreased. Methods: We summarized the alterations of classical neurotransmitters in the brain regions involved in cognitive, depressive and psychotic symptoms in Alzheimer’s disease. Starting from these neurotransmitter alterations, we describe neural networks including specific serotonergic subreceptors in the involved brain regions. Results: In the hippocampus and prefrontal cortex, serotonin levels are associated with cognitive functions, whereas in the brainstem serotonin levels are related with affective symptoms. Psychotic symptoms which can occur in patients with Alzheimer’s disease are associated with dopamine and serotonin hyperactivity in the mesolimbic system and hippocampus. The interaction between classical neurotransmitters and their specific subreceptors is shown in different brain areas. Conclusion: In clinical trials, the therapeutic effects of 5-HT4, 5-HT7 agonists and 5-HT3, 5-HT6 antagonists have been examined to improve cognitive symptoms in Alzheimer’s disease. In these trials, 5-HT4 agonists and 5-HT4 antagonists showed a significant better effect in improving cognitive functions than placebo. The effect of such drugs on the formation of amyloid plaques is also examined. The appropriate use of antidepressant and antipsychotic drugs with an agonism or antagonism at specific serotonergic subreceptors is pointed out. Serotonin-selective antidepressant drugs significantly improve depressant symptoms and daily activities in Alzheimer patients and they are used to treat aggressive behaviour. Among the second-generations antipsychotic drugs (D2 and 5-HT2A antagonists), drugs with a favorable metabolic profile should be used.

Development of novel pharmacotherapies for the treatment of traumatic injury to the nervous system has been ongoing for over 40 years. Despite many promising compounds discovered using animal models, no treatments have successfully translated into the clinic. The central dogma in this field is that brain trauma initiates a complex chain of biochemical events leading to secondary brain damage and sustained neurological deficits. The delayed secondary brain injury is likely to result from multiple insults including oxidative stress, mitochondrial dysfunction, breakdown of the blood brain barrier, dysregulated release of glutamate, pro-inflammatory cytokines, and other mediators. However, therapies targeting these systems have generally met with failure in clinical trials. The purpose of this review is to summarize the models used for preclinical neurotrauma research, provide a brief overview of previous failed clinical trials in head and spinal cord injury, and finally, to review involvement of the cholinergic system and discuss implications for future research. Possibilities and pitfalls of targeting the cholinergic system for neuroprotection and/or enhancement of functional recovery are also discussed.

Existing treatments of traumatic brain injury (TBI) have failed to reverse tremendous losses in productivity, independence and overall quality of life among TBI victims and therefore, cannot be viewed as sufficient. Although there is no shortage of promising basic concepts that may translate to efficacious therapies after TBI, the accumulated knowledge has yet to deliver treatments that adequately meet clinical and social demands. In this article, we discuss novel concepts, recent advances and accompanying challenges in developing cholinergic and related therapies after TBI.

Currently availably antipsychotic drugs are effective in ameliorating the positive symptoms of schizophrenia. Nevertheless, the cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. In particular, potential cognitive enhancers have received considerable attention in the field of schizophrenia research. From among the multiple therapeutic approaches that have recently been proposed, this review will focus on serotonin receptors, namely 5-HT5ARs, 5-HT6Rs and 5-HT7Rs, and on alpha 7 nicotinic acetylcholine receptors (α7-nAChRs). The purpose of this review is to summarise existing data regarding the effects of ligands of these receptors on measures of schizophrenia-like behaviours in animal models, with particular emphasis on their procognitive effects. Existing clinical data will also be reported, and the potential clinical efficacy of these compounds will be discussed with regard to the preclinical results. Possible explanations for the lack of clinically validated evidence and for the discrepancies between the clinical and preclinical data will also be provided.

Many of the most debilitating symptoms for psychiatric disorders such as schizophrenia remain poorly treated. As such, the development of novel treatments is urgently needed. Unfortunately, the costs associated with high failure rates for investigational compounds as they enter clinical trials has led to pharmaceutical companies downsizing or eliminating research programs needed to develop these drugs. One way of increasing the probability of success for investigational compounds is to incorporate alternative methods of identifying biological targets in order to more effectively screen new drugs. A promising method of accomplishing this goal for psychiatric drugs is to use functional magnetic resonance imaging (fMRI). fMRI investigates neural circuits, shedding light on the biology that generates symptoms such as hallucinations. Once identified, relevant neural circuits can be targeted with pharmacologic interventions and the response to these drugs measured with fMRI. This review describes the early use of fMRI in this context, and discusses the alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), as an example of the potential value of fMRI for psychiatric drug development.

Background: Cognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms. Methods: We review the literature supporting the dysfunction of the cholinergic system in schizophrenia, discuss the preclinical and clinical data showing that modulating the cholinergic system could improve the symptoms of schizophrenia and review the main pharmacological strategies being investigated to treat cholinergic dysfunction in schizophrenia. Results: Post-mortem and neuroimaging studies suggest there are widespread reductions in cholinergic receptor signalling in the cortex as well as subcortical regions, such as the hippocampus and striatum, in individuals with schizophrenia. Potential cholinergic drug targets are being pursued to increase receptor function. These include inhibiting the activity of the enzyme acetylcholinesterase to increase synaptic acetylcholine levels, and increasing the nicotinic receptor and muscarinic receptor activity with agonists or positive allosteric modulators. Conclusion: Amongst the most promising drug targets for treating schizophrenia are the α7 nicotinic receptor and the CHRM1 and CHRM4 muscarinic receptors. The recent development of allosteric modulators that selectively target these receptors offers the potential to more effectively treat the symptoms of schizophrenia.

Homomeric α7 nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation of cognitive processes such as memory and attention and have potential as therapeutic targets for the treatment of the cognitive deficits associated with schizophrenia. Though numerous α7 nAChR agonists have been developed, and several have progressed to clinical trials, these are derived from few common chemotypes. Consequently, many of these α7 nAChR clinical candidates share unfavorable side-effect profile. SEN12333 represents a novel chemotype for the development of α7 nAChR agonists, and exploration of this scaffold has produced structurally diverse ligands with promising pharmacological properties. This review will summarize structure-affinity and -activity relationships surrounding analogs of SEN12333.

Lung cancers express an autocrine cholinergic loop in which secreted acetylcholine can stimulate tumor growth through both nicotinic and muscarinic receptors. Because activation of mAChR and nAChR stimulates growth; tumor growth can be stimulated by both locally synthesized acetylcholine as well as acetylcholine from distal sources and from nicotine in the high percentage of lung cancer patients who are smokers. The stimulation of lung cancer growth by cholinergic agonists offers many potential new targets for lung cancer therapy. Cholinergic signaling can be targeted at the level of choline transport; acetylcholine synthesis, secretion and degradation; and nicotinic and muscarinic receptors. In addition, the newly describe family of ly-6 allosteric modulators of nicotinic signaling such as lynx1 and lynx2 offers yet another new approach to novel lung cancer therapeutics. Each of these targets has their potential advantages and disadvantages for the development of new lung cancer therapies which are discussed in this review.

Lung cancer is the leading cause of cancer-related deaths worldwide. Smoking accounts for approximately 70% of the cases of non– small cell lung cancer (NSCLC) and 90% of the cases of small-cell lung cancer (SCLC), although some patients develop lung cancer without a history of smoking. Nicotine is the most active addictive component of tobacco smoke. It does not initiate tumorigenesis in humans and rodents, but it alters the pathophysiology of lung cells by inducing the secretion of growth factors, neurotransmitters and cytokines, and promotes tumour growth and metastases by inducing cell cycle progression, migration, invasion, angiogenesis and the evasion of apoptosis. Most of these effects are a result of nicotine binding and activation of cell-surface neuronal nicotinic acetylcholine receptors (nAChRs) and downstream intracellular signalling cascades, and many are blocked by nAChR subtype-selective antagonists. Recent genome-wide association studies have revealed single nucleotide polymorphisms of nAChR subunits that influence nicotine dependence and lung cancer. This review describes the molecular basis of nAChR structural and functional diversity in normal and cancer lung cells, and the genetic alterations facilitating smoking-induced lung cancers. It also summarises current knowledge concerning the intracellular pathways activated by nicotine and other compounds present in tobacco smoke.

Background: It is actually known that acetylcholine works as a signaling molecule in non-neuronal cells and tissues, in addition to its neuronal function as neurotransmitter. It can act on two types of receptors nicotinic and muscarinic receptors (mAChRs). The latter belong to the G protein coupled receptor family and there are five subtypes genetically cloned. Their activation triggers classical and non-classical intracellular signals that could be linked to the proliferation of normal and/or transformed cells. The M3 subtype was identified in different types of tumors and its stimulation with agonists triggers cell proliferation, migration, invasion and metastasis. Results: Our laboratory has extensively investigated the expression and function of mAChRs in breast tumors from animal and human origins. We found a profuse expression of mAChRs in breast tumors, but opposite to this, an absence of these receptors in normal breast cells and tissues. The stimulation of mAChRs with the cholinergic agonist carbachol for 20 h increased tumor cell death. Moreover, the combination of subthreshold concentrations of the agonist with paclitaxel potentiates cell death. The usage of low dose chemotherapy with short drug free intervals was named metronomic therapy and it has emerged as a novel regimen for cancer treatment with very low incidence of side effects. Conclusion: Our work and that of others indicate that mAChRs that are over-expressed in different types of tumor cells could be a useful target for metronomic therapy in cancer treatment.

Background: Glaucoma is characterized as a neuropathic disease that causes progressive degeneration of retinal ganglion cells (RGCs) in the retina, resulting in irreversible loss of vision. All conventional treatments for glaucoma are focused on reducing intraocular pressure (IOP) in the anterior chamber of the eye. However, these treatments alone are insufficient to halt the progression of the disease. As a result, neuroprotective strategies have been developed that prevent retinal neuron loss and disease progression. Methods: The goal of this review is to summarize and discuss neuroprotective strategies in glaucoma at the level of the retina and the ganglion cell layer instead of treatments targeting IOP. Recent and past neuroprotective therapies used to prevent the loss of retinal ganglion cells, the loss of axons in the optic nerve and the loss of vision and function associated with glaucoma are presented. Results: Pharmacological approaches have targeted specific receptors, signaling cascades and neurotrophic factors to induce neuroprotection in the retina, while others have focused on the mechanism of cellular loss associated with glaucoma, including excitotoxicity, oxidative stress and apoptotic processes. In addition to neuroprotective pharmacological treatments, stem cell, gene therapy and viral research have demonstrated neuroprotection against the loss of RGCs in glaucomatous conditions. Conclusion: It is likely that future development for glaucoma treatment will include a combination of these treatments to prevent the pathophysiology of glaucoma.