Neuropeptide Y receptors as targets of obesity treatment

The prevalence of obesity continues to increase throughout the world and the burden of obesity and related co-morbidities is large. However, existing drug therapies for obesity are limited, and agents with high efficacy, safety and tolerability are expected to better meet patient needs and lead to more substantial commercial success. Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Multiple receptor subtypes mediate the effects of NPY on energy homeostasis and many pharmacological studies indicate the involvement of Y1 and Y5 receptor subtypes in NPY-induced feeding and obesity. In addition, recent observations with gut-derived peptides suggest a role for Y2 and Y4 receptor subtypes as catabolic receptors. This article highlights and reviews recent observations and patents regarding NPY receptor ligands for drug discovery as antiobesity agents.     

Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y₁–y₆). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y₁ and Y₅ receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y₁ and Y₅ receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y₁ receptor or the neuropeptide Y Y₅ receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y₁ receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.     

Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development of novel types of anti-inflammatory drugs are also discussed.     

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.     

Metabotropic glutamate 2/3 receptors as drug targets

Metabotropic glutamate receptors are a family of class III G-protein-coupled receptors comprising eight members (mGluR1-8), which are an attractive target in the central nervous system because of the widespread use of glutamate as the principal excitatory amino acid transmitter. The unique pharmacology of class III G-protein coupled receptors, their forebrain localization in key limbic-related cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle modulation of glutamatergic neurotransmission make these receptors intriguing targets for a wide variety of neuropsychiatric disorders.     

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.     

Nicotinic acetylcholine receptors as drug targets

While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.     

Metabotropic glutamate receptors as drug targets

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na(+) (Ca(2+)) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.     

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.     

NPY receptors as potential targets for anti-obesity drug development

The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review.     

Metabotropic glutamate receptors as targets for new drug development

The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.     

The opioid receptors as targets for drug abuse medication

The endogenous opioid system is largely expressed in the brain, and both endogenous opioid peptides and receptors are present in areas associated with reward and motivation. It is well known that this endogenous system plays a key role in many aspects of addictive behaviours. The present review summarizes the modifications of the opioid system induced by chronic treatment with drugs of abuse reported in preclinical and clinical studies, as well as the action of opioid antagonists and agonists on the reinforcing effects of drugs of abuse, with therapeutic perspectives. We have focused on the effects of chronic psychostimulants, alcohol and nicotine exposure. Taken together, the changes in both opioid peptides and opioid receptors in different brain structures following acute or chronic exposure to these drugs of abuse clearly identify the opioid system as a potential target for the development of effective pharmacotherapy for the treatment of addiction and the prevention of relapse.     

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。     

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.     

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.