Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy.     

以核受体为靶标的胆汁淤积治疗药物研究进展

胆汁淤积的治疗药物匮乏,熊去氧胆酸是目前唯一被FDA通过的治疗原发性胆汁性肝硬化的药物,但其药效却限于疾病早期,因此迫切需要开发新的胆汁淤积治疗药物。核受体能调控胆汁酸稳态,它作为胆汁淤积治疗的靶标是目前研究的热点。该综述对目前报道最多的核受体进行总结,分析其作为胆汁淤积药物治疗靶标的利弊及应用前景。     

Nuclear receptors as therapeutic targets for Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is associated with perturbations in synaptic function, impairments in energy metabolism and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment. AREAS COVERED: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiology. EXPERT OPINION: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degradation of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clinical trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the negative outcome of the Phase III clinical trials are likely to diminish interest in pursuing this target.     

Neuronal nicotinic acetylcholine receptors as drug targets

Neuronal nicotinic acetylcholine receptors (nAChRs) are an important class of ion channels that have been associated with a number of neurological conditions. A great deal of research has been focused on attempting to understand the exact physiological role of these receptors. As drug targets, the nAChRs are quite complex, both in their structure (multiple receptor subtypes) and their physiological function. Initially, the difficulty encountered in identifying small-molecule modulators led to doubts about the validity of this class of receptors as drug targets. More recently, in vitro and in vivo data, homology modelling, and the identification of small-molecule agonists, have confirmed nAChRs as valid drug discovery targets. In fact, several compounds are now in clinical development for the treatment of pain, smoking cessation and cognitive disorders.     

Toll-like receptors as therapeutic targets in gastrointestinal diseases

Importance of the field: Toll-like receptors (TLRs) are innate immunity receptors that recognize several different antigens, initiating immunological/inflammatory responses. Recent evidence associates numerous pathophysiological processes and diseases with dysregulated activation of these receptors, conferring a potential therapeutic value to their modulation.

Areas covered in this review: The aim of this systematic review that covers literature from the past 10 years is to address the role of TLRs in the pathophysiology of gastrointestinal (GI) diseases as well as the therapeutic potential of modulating TLRs' signaling pathways in GI pathology.

What the reader will gain: This review shows that TLRs play an important role in the pathophysiology of several GI diseases and that modulating TLRs signaling pathways may have an enormous therapeutic potential. Different methods for modulation of TLRs' activity in GI tract, with direct agonists/antagonists but also with non-specific substances, like antibiotics or probiotics, are presented.

Take home message: Even though TLRs modulators have been used for therapy in some GI diseases, further research, particularly in humans, is needed in order to establish the precise role of the different TLRs in the diverse GI diseases and to motivate clinical trials that consider TLRs as therapeutic targets in GI pathology.     

G-protein-coupled receptors as therapeutic targets for glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour in adults. Treatments include surgical resection, radiotherapy, and chemotherapy. Despite this, the prognosis remains poor, with an impacted quality of life during treatment coupled with brain tumour recurrence; thus, new treatments are desperately needed. In this review, we focus on recent advances in G-protein-coupled receptor (GPCR) targets. To date, the most promising targets are the chemokine, cannabinoid, and dopamine receptors, but future work should further examine the melanocortin receptor-4 (MC4R), adhesion, lysophosphatidic acid (LPA) and smoothened (Smo) receptors to initiate new drug-screening strategies and targeted delivery of safe and effective GBM therapies.     

Adenosine receptors as targets for drug development

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A(1), A(2A), A(2B) and A(3). Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma.     

The next generation beneficial actions of novel probiotics as potential therapeutic targets and prediction tool for metabolic diseases

The prevalence of metabolic disease has rising and affected over 1,000 million populations globally. Since the metabolic disease and its related complication are board, it has become the major health hazard of modern world. However, Long term medication of metabolic disease may cause serious side effects and risk for adverse health problems. Recently, emerging studies focus on exploring the mechanistic details of metabolic state in disease development and progression. Gut bacteria ecosystem was considered to play a pivotal role in regulating energy homeostasis and great associated with the development of metabolic disease. Accumulated evidences indicated that Akkermansia muciniphila, Faecalibacterium prausnitzii, and Roseburia hominis improve the balance of the microecology in the intestine of the host and have positive effects on enhancing nutrients absorption. Hence, the novel probiotics as therapeutic target to modify gut microbiota generally focus on improving microbiota dysbiosis, and offers new prospects for treating metabolic disease. In the present review, we discuss the significant roles and regulatory properties of specific bacterium in the context of intestinal microbial balance, explores the kinds of harmful/beneficial bacteria that were likely to act as indicator for metabolic disease. Further proposed a stepwise procedure in the basis of sequencing technology with that of innovative option to reestablish the microbial equilibrium and prevent metabolic disease.     

Nicotinic receptors as targets for therapeutic discovery

Nicotinic acetylcholine receptors (nAChRs) represent a class of therapeutic targets with the potential to impact numerous diseases and disorders where significant unmet medical needs remain. The latter include cognitive and neurodegenerative diseases; psychotic disorders, such as schizophrenia; acute nociceptive, neuropathic and inflammatory pain; affective disorders, such as depression and inflammation, where nAChR subtypes modulate key cellular pathways involved in anti-inflammatory processes as well as cell survival. Our increased understanding of the heterogeneity of nAChR targets is defining the relationship of biologic effects to specific receptor subtypes, which in turn, will allow further refinement of desired therapeutic activities. Both preclinical and clinical evidence support the notion that novel compounds targeting specific nAChR subtypes will offer increased potency and efficacy, longer lasting effects, fewer side effects and a more rapid onset of action and less dependence, compared with existing therapies. Clinical proof-of-concept is rapidly emerging and will solidify the position of this new therapeutic approach.     

Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells

Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.     

Adenosine receptors as targets for drug discovery.

This symposium was held on March 30, 1998 as part of the 215th American Chemical Society National Meeting. It was presided by PR McGuirk of Pfizer and was particularly aimed at medicinal chemists. There were more than 200 attendees at the symposium.     

Thrombin receptors as drug discovery targets

Summary A G-protein-coupled thrombin receptor has been identified, cloned and shown to be present on platelets, endothelial cells, fibroblasts and vascular smooth muscle cells. -Thrombin binds to this receptor via thrombin's anion-binding exosite and catalyzes exposure of a new NH₂-terminus. The new receptor NH₂-terminus acts as an agonistic tethered ligand that comprises part of the receptor it activates. The first five or more amino acids of the new NH₂-terminus (beginning with SFLLR in the human receptor) can directly activate the receptor in the absence of thrombin. Because thrombin receptor activation may participate in thrombosis, inflammation and fibroproliferative disorders, research is being conducted on several strategies that might interfere with the receptor-mediated pathophysiologic actions of thrombin. The structure-activity relationship for thrombin receptor agonist peptides has been studied in detail, and some general requirements for agonist activity have emerged. Although several peptide-based thrombin receptor antagonists have been described, these earliest examples are not very potent and they appear to be partial agonists in cells other than platelets. Despite the limitations of these prototypes, initial studies with such compounds have demonstrated the importance of this thrombin receptor in -thrombin-mediated activation of platelets and certain other cells and in arterial thrombosis.     

Peroxisome proliferator-activated receptor δ (PPARδ), a novel target site for drug discovery in metabolic syndrome

The development of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and diabetes mellitus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR)α and γ agonists have shed light on the treatment of hypertriglyceridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPARδ functions is lagging behind because specific PPARδ agonists have not been developed. The appearance of new PPARδ agonists is brightening the prospects for elucidating the physiological role of PPARδ. PPARδ is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation in skeletal muscle and adipose tissue by PPARδ agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough. It seems that treatment of PPARδ agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role of PPARδ may be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPARδ agonists against metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions of PPARδ itself and its agonists in the future.     

Galanin receptors as a potential target for neurological disease

Introduction: Galanin is a 29/30 amino acid long neuropeptide that is widely expressed in the brains of many mammals. Galanin exerts its biological activities through three different G protein-coupled receptors, GalR1, GalR2 and GalR3. The widespread distribution of galanin and its receptors in the CNS and the various physiological and pharmacological effects of galanin make the galanin receptors attractive drug targets.

Areas covered: This review provides an overview of the role of galanin and its receptors in the CNS, the involvement of the galaninergic system in various neurological diseases and the development of new galanin receptor-specific ligands.

Expert opinion: Recent advances and novel approaches in migrating the directions of subtype-selective ligand development and chemical modifications of the peptide backbone highlight the importance of the galanin neurochemical system as a potential target for drug development.     

Nuclear receptors and drug metabolism for the personalization of cancer therapy

Introduction: A remarkable inter-individual variability in the occurrence of severe side effects represents an ongoing challenge in cancer treatment. Significant research efforts have focused on elucidating the contribution of the host genetic variability, but only a few markers have been identified for use in clinical practice. Several studies demonstrated that PXR and CAR activation can affect the expression of genes involved in absorption, distribution, metabolism and excretion (ADME) of antineoplastic drugs. The study of the host genetic background of Pregnane X Receptor (PXR; NR1I2) and Constitutive Androstane Receptor (CAR; NR1I3 and NR1I4), represents a new and attractive strategy to discern variability in ADME of antineoplastic drugs.

Areas covered: An update of the most important findings about investigational CAR and PXR pharmacogenetic markers of anti-cancer drugs toxicity is provided.

Expert opinion: A differential activation of PXR and CAR can affect the pharmacokinetics and pharmacodynamics of antineoplastic drugs. Pharmacogenetics studies published up to date provide encouraging even if exploratory results. Future large and prospective studies will clarify the clinical value of PXR and CAR genetic markers in treatment personalization.     

Nuclear receptors as potential targets for modulating reverse cholesterol transport

This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis. Nuclear receptors of the RXR heterodimer family have recently been shown to regulate key genes involved in HDL metabolism and reverse cholesterol transport. These include the PPARs (peroxisome proliferator activated receptors), the LXR (liver X receptor) and the farnesoid X receptor (FXR). The synthesis of specific and potent ligands for these receptors has aided in ascertaining the physiological role of these receptors as lipid sensors and the potential therapeutic utility of modulators of these receptors in dyslipidemias and cardiovascular disease.