瞬时受体电位香草酸亚型1（TRPV1）与N-甲基-D-天冬氨酸（NMDA）受体相互作用的研究进展

辣椒素是从辣椒中提取的天然产品,可以激活瞬时受体电位香草酸亚型1(TRPV1)受体,它们的分子作用模式涉及重要的生理过程,这些过程是疼痛和内源性调节机制的基础。TRPV1和N-甲基-D-天冬氨酸(NMDA)受体均广泛分布和表达于多种组织器官中,均具有较为复杂的生物学功能,这也预示着它们之间关系的探索,将为更多实验研究提供理论基础,并对新型药物的研发及临床应用有着深远意义。总结了TRPV1与背根神经节NMDA受体之间相互作用与瑞芬太尼痛觉过敏的关系、与神经毒性和神经保护间的关系以及与抗焦虑样效应间的关系的研究进展。     

Disease-related changes in TRPV1 expression and its implications for drug development

The transient receptor potential vanilloid 1 (TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non-neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiological functions. Here, we summarize the evidences for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of diseases.     

Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain

The transient receptor potential vanilloid 1 receptor (TRPV1) plays an important role in inflammatory heat hyperalgesia. TRPV1 is a non-selective cation channel gated by noxious heat, protons and capsaicin, thus being regarded as a polymodal molecular integrator in nociception. Abundant evidence has demonstrated that TRPV1 is also modulated by numerous inflammatory mediators, including growth factors, neurotransmitters, peptides or small proteins, lipids, chemokines and cytokines. By activating multiple protein kinases to increase the phosphorylation of TRPV1, pronociceptive inflammatory mediators sensitise the TRPV1 response to noxious heat, protons and capsaicin, thus augmenting thermal hyperalgesia. In contrast, by inhibiting protein kinases or other mechanisms, antinociceptive inflammatory mediators suppress the response of TRPV1 to these stimuli, thus damping thermal hyperalgesia. The positive modulation of TRPV1 by inflammatory mediators may constitute a novel mechanism underlying sustained inflammatory or neuropathic pain. Blocking pronociceptive inflammatory mediator-exerted sensitising effects or boosting antinociceptive inflammatory mediator-induced suppressing effects on TRPV1 should be considered as sources of novel potential therapies to more effectively treat chronic pain conditions.     

TRPV1 function in health and disease

The transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater than approximately 43°C., or capsaicin, the pungent ingredient of hot chilli peppers. More importantly, however, it has been shown that TRPV1 plays a pivotal role in the development of the burning pain sensation associated with inflammation in peripheral tissues. More recently, there has been a virtual avalanche of sightings of TRPV1 on the anatomical landscape, coupled with association of TRPV1 with a wide range of non-pain-related physiological and pathological conditions. Here, we consider the continuously expanding set of functions in both health and disease which TRPV1 is understood to subserve at present. The widespread expression of TRPV1 in the human suggests that, in addition to the development of burning pain associated with acute exposure to heat or capsaicin, and with inflammation, TRPV1 may also be involved in an array of vitally important functions, such as those of the urinary tract, the respiratory and auditory systems. Moreover, TRPV1 could also be involved in the maintenance of body and cell homeostasis, metabolism, regulation of hair growth, and development of cancer. Thus, controlling TRPV1 function may possess the potential of providing exciting opportunities for therapeutic interventions. At the same time, however, the widespread distribution of these ion channels introduces a tremendous complication in developing a drug to serve in one disease context which may have profound implications for normal TRPV1 functioning in other non-pathological contexts.     

TRPV1b, a functional human vanilloid receptor splice variant

Transient receptor potential (TRP) genes encode a family of related ion-channel subunits. This family consists of cation-selective, calcium-permeable channels that include a group of vanilloid receptor channels (TRPV) implicated in pain and inflammation. These channels are activated by diverse stimuli, including capsaicin, lipids, membrane deformation, heat, and protons. Six members of the TRPV family have been identified that differ predominantly in their activation properties. However, in neurons, TRPV channels do not account for the observed diversity of responses to activators. By probing human and rat brain cDNA libraries to identify TRPV subunits, we identified a novel human TRPV1 RNA splice variant, TRPV1b, which forms functional ion channels that are activated by temperature (threshold, approximately 47 degrees C), but not by capsaicin or protons. Channels with similar activation properties were found in trigeminal ganglion neurons, suggesting that TRPV1b receptors are expressed in these cells and contribute to thermal nociception.     

Attenuation of anxiety-related behaviour after the antagonism of transient receptor potential vanilloid type 1 channels in the rat ventral hippocampus

The neurochemical mechanisms supporting the role of the ventral hippocampus in anxiety are now under investigation. To address this issue, we examined whether the pharmacological blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the ventral hippocampus would attenuate anxiety-related behaviour. Rats infused with the TRPV1 channel antagonist capsazepine (2.0 nmol) showed less inhibitory avoidance than controls in the elevated plus-maze test. This result indicates an anxiolytic-like effect, and suggests a role for TRPV1 channels in regulating anxiety.     

TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications

The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by capsaicin, heat, protons and endogenous ligands such as anandamide. It is largely expressed in the urinary tract of mammals. Structures in which the receptor expression is firmly established include sensory fibers and urothelial cells, although the presence of TRPV1 in other cell types has been reported. As in other systems, pain perception was the first role attributed to TRPV1 in the urinary tract. However, it is now increasingly clear that TRPV1 also regulates the frequency of bladder reflex contractions, either through direct excitation of sensory fibers or through urothelial-sensory fiber cross talk involving the release of neuromediators from the epithelial cells. In addition, the recent identification of the receptor in urothelial and prostatic cancer cells raise the exciting hypothesis that TRPV1 is involved in cell differentiation. Desensitization of the receptor by capsaicin and resiniferatoxin has been investigated for therapeutic purposes. For the moment, lower urinary tract dysfunctions in which some benefit was obtained include painful bladder syndrome and overactive bladder of neurogenic and non-neurogenic origin. However, desensitization may become obsolete when non-toxic, potent TRPV1 antagonists become available.     

The functions of TRPA1 and TRPV1: moving away from sensory nerves

The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation.     

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

In peripheral sensory neurons, the vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) functions as a molecular integrator of painful stimuli, including those mediated by capsaicin, acid, and heat. Antagonist blockade of TRPV1 activation is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. TRPV1 is also expressed, albeit at lower levels, in the brain and in non‐neuronal tissues, where its function(s) remains elusive. The contribution of TRPV1 receptor activity to physiological reflexes and disease states is complex and is only beginning to be understood. Consequently, the resultant effects of TRPV1 antagonists on the body may be unforeseen. Indeed, clinical trials with a number of TRPV1 antagonists were recently terminated due to their marked hyperthermic activity. In this review article, the medicinal chemistry of TRPV1 antagonists is discussed inasmuch as it relates to the efficacy, safety, tolerability and potential side effects of these compounds. In addition, the available information on the current status of the clinical trials with TRPV1 antagonists is summarized. Drug Dev Res 68:477–497, 2007. © 2008 Wiley‐Liss, Inc.     

Analgesic potential of TRPV3 antagonists

The vanilloid subfamily of transient receptor potential (TRPV) ion channels serves critical functions in sensory signaling in specialized cells and intact organisms ranging from yeast to primates. As thermosensors, chemosensors, and/or mechanosensors, these channels monitor the local environment and integrate and respond to multiple stimuli distinctively. More than a decade of research on the founding member of the subclass, TRPV1, has led to advancement of multiple antagonists into the clinic for the treatment of chronic pain. In recent years the comprehensive knowledge accessed through these studies has been applied to enhance understanding of other TRPV isoforms and, in particular, to determine whether they, too, represent promising targets for drug discovery. This review focuses on emerging data that define a role for TRPV3 in transducing signals in pain pathways and identify antagonists that demonstrate efficacy in relevant preclinical behavioral models.     

Advances in the development of TRPV1 antagonists

Transient receptor potential V1 (TRPV1) is a nonspecific cation channel subject to polymodal activation. TRPV1, originally termed vanilloid receptor 1, can be activated by the prototypical vanilloid capsaicin as well as decreases in extracellular pH and increases in temperature. The neuronal expression and biology surrounding TRPV1 suggest that it plays a significant role in the establishment and maintenance of various pain states as well as a potential role for TRPV1 in cough and bladder function. This review outlines the potential mechanism(s) by which activation of TRPV1 leads to pain and hyperalgesia, lessons learned via the development of antagonists and the current status of the development of therapeutic entities for validation within a clinical setting.     

Drug design and development through the vanilloid receptor

The vanilloid receptor (TRPV1) has attracted a great expectation in pain therapeutics for the treatment of chronic inflammatory conditions. As a result, several drug discovery programmes were launched in the past years that yielded a large number of receptor agonists and antagonists. However, despite the claimed therapeutic potential of TRPV1 modulators, a disappointing number of candidates have progressed into clinical trials and those were only for dental pain and migraine, indicating that our understanding of the role of TRPV1 in pain is still very limited. The widespread distribution of TRPV1 in different tissues suggests an involvement in body functions other than pain. Indeed, new findings indicate that TRPV1 is tonically active in physiological conditions and its pharmacological blockade leads to hyperthermia. Furthermore, the full abrogation of TRPV1 in some models of chronic pain results in enhanced pain. Therefore, a remaining challenge is the development of drugs that preserve the physiological activity of TRPV1 and downregulate the function of overactive receptors.     

瞬时受体电位香草酸亚型1在炎症中的作用

瞬时受体电位香草酸亚型1 （TRPV1）作为细胞信号的多调受体,可被多种物理、化学因素激活或致敏,从而引起细胞外Ca2＋顺电化学梯度向细胞内流动,介导细胞的基本活动,在慢性炎症反应性疾病中发挥重要作用.近年来,研究表明TRPV1具有抑制炎症、保护机体的功能.     

Small molecule vanilloid TRPV1 receptor antagonists approaching drug status: can they live up to the expectations?

The cloning of the transient receptor potential vanilloid type-1 (TRPV1) receptor initiated the discovery of potent small molecule antagonists, many of which are in preclinical phase or already undergoing clinical trials. While animal experiments imply a therapeutic value for these compounds as novel analgesic-antiphlogistic drugs, new findings with TRPV1 deficient (trpv1 -/-) mice signal troubles for TRPV1 antagonists as clinical research gains impetus. An emerging concept with important implications for drug development is that TRPV1 may be differentially regulated under physiological and pathological conditions. If so, it is conceivable that such TRPV1 ligands can be synthesized that specifically target TRPV1 in diseased (e.g. inflamed or neoplastic) tissues but spare TRPV1 that subserves its physiological functions in healthy organs. This review explores the current status of this field and seeks an answer to the question how these new discoveries could be factored into TRPV1 drug discovery and development.     

A "cute" desensitization of TRPV1

Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process.     

Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbumin-sensitized guinea pig

BACKGROUND AND PURPOSE Airway sensory nerves play a key role in respiratory cough, dyspnoea, airway hyper-responsiveness (AHR), all fundamental features of airway diseases [asthma and chronic obstructive pulmonary disease (COPD)]. Vagally mediated airway reflexes such as cough, bronchoconstriction and chest tightness originate from stimulation of airway sensory nerve endings. The transient receptor potential vanilloid 1 receptor (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological therapy of AHR in airway disease. EXPERIMENTAL APPROACH As guinea pig models can provide some of the essential features of asthma, including AHR, we have established the model with some classical pharmacological agents and examined the effect of the TRPV1 antagonists, SB-705498 and PF-04065463 on AHR to histamine evoked by ovalbumin (OA) in unanaesthetized sensitized guinea pigs restrained in a double chamber plethysmograph. Specific airway conductance (sGaw) derived from the airflow was calculated as a percentage of change from baseline. KEY RESULTS Cetirizine and salbutamol significantly inhibited OA-evoked bronchoconstriction [sGaw area under the curve (AUC): 70 and 78%, respectively]. Atropine, SB-705498 and PF-04065463 significantly inhibited OA-evoked AHR to histamine in unanaesthetized, OA-sensitized guinea pigs (sGaw AUC: 94%, 57% and 73%, respectively). Furthermore, this effect was not related to antagonism of histamine's activity. CONCLUSION AND IMPLICATIONS These data suggest that TRPV1 receptors located on airway sensory nerves are important in the development of AHR and that modulation of TRPV1-receptor activity represents a potential target for the pharmacological therapy of AHR in airway disease.     

The diversity in the vanilloid (TRPV) receptor family of ion channels

Following cloning of the vanilloid receptor 1 (VR1) at least four other related proteins have been identified. Together, these form a distinct subgroup of the transient receptor potential (TRP) family of ion channels. Members of the vanilloid receptor family (TRPV) are activated by a diverse range of stimuli, including heat, protons, lipids, phorbols, phosphorylation, changes in extracellular osmolarity and/or pressure, and depletion of intracellular Ca2+ stores. However, VR1 remains the only channel activated by vanilloids such as capsaicin. These channels are excellent molecular candidates to fulfil a range of sensory and/or cellular roles that are well characterized physiologically. Furthermore, as novel pharmacological targets, the vanilloid receptors have potential for the development of many future disease treatments.     

Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides

The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).