Current Topics in Medicinal Chemistry - Volume 5, Issue 6, 2005
Volume 5, Issue 6, 2005
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Editorial [Hot Topic: New Frontiers in Managing Chronic Pain (Guest Editor: Gerald W. Zamponi)]
More LessMost people will experience severe pain at some point throughout their lives. Pain can be loosely classified into “good” and “bad” pain. The former serves as a key warning system that protects us from injury. Without “good” pain, nothing would stop us from reaching into a pot of boiling oil. “Bad” pain is a form of pain that arises as a result of a chronic injury and results in persistent excitation of pain pathways. This type of pain is referred to as chronic and no longer fulfills the purpose of warning us of acute danger. Chronic pain afflicts tens of millions of Americans, however, to date, the therapeutic options remain limited and drugs that are efficacious in treating chronic pain are often associated with side effects or the development of tolerance. As a result, the drug discovery sector is actively engaged in finding novel treatments for chronic pain, and in identifying new targets. In this issue, we focus on some of the promising targets for the development of novel therapeutics to manage chronic pain. These potential targets range from voltage and ligand gated ion channels, to transporters, and G protein coupled receptors. Sodium channels are key contributors to the firing of nociceptive neurons, and persistent sodium channels have received increased attention as targets for pain treatment. Wood and Boorman highlights the role of persistent sodium channels in chronic pain, and presents a detailed overview of molecular and pharmacological aspects of sodium channel function. Voltage gated calcium channels are involved in the pain pathway in multiple ways. N-type channels are responsible for neurotransmitter release from presynaptic sites. These channels are the target of the recently FDA approved peptide drug Prialt. T-type channels regulate neuronal excitability and firing, and hence their inhibition is predicted to be antinociceptive. These developments are highlighted by Bourinet and Zamponi. Price and colleagues also exploit excitability of nociceptive neurons, but from the point of view of cation-chloride-cotransporters which are functionally coupled to GABAA receptors. Blocking synaptic transmission at postsynaptic sites may also provide an avenue for blocking nociceptive signaling. In this vein, the article by Salter focuses on protein-protein interactions involving the NMDA receptor as putative targets for regulating pain transmission at the spinal level. During inflammation, a host of proteases are released that can activate proteinase activated receptors. Cenac and Vergnolle examine the roles of protease activated receptors in the pain pathway, and suggest avenues by which these receptors might be exploited as suitable targets for analgesics. Sah and colleagues give a detailed overview of the role of neurotrophic factors in the pain pathway, and finally, the article by Cashman focuses on structure activity aspects concerning morphine-6- glucuronide analogs, a potentially novel class of analgesics. Despite tremendous activity in the area of pain research, no universal pharmacological inhibitor of pain is currently on the market. Moreover, it has remained a challenge to identify small organic, orally available molecules which are clinically active without producing side effects. Alternative avenues, may however present themselves through increased availability of gene therapies designed to depress expression of receptors and/or ion channels highlighted in this issue.
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Voltage-Gated Sodium Channel Blockers; Target Validation and Therapeutic Potential
Authors: John N. Wood and James BoormanVoltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signalling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. In addition, cardiac arrhythmias and epileptic activity can be treated with sodium channel blockers. As we have learned more about the sub-types of sodium channels and their distribution, new therapeutic opportunities have suggested themselves. There are indications that sodium channel blockers may also be useful in affective disorders and schizophrenia. The production of tissue-specific and eventually inducible knock out mice as well as genetic studies has proved useful in understanding the specialised role of individual types of sodium channels. The development of sub-type specific blockers has proved slower than anticipated, although the properties of naturally occurring toxin blockers suggest that subtype-specific blockers of sodium channels could be very useful clinically in the treatment of pain.
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Voltage Gated Calcium Channels as Targets for Analgesics
Authors: Emmanuel Bourinet and Gerald W. ZamponiManagement of pain is an essential aspect of medicine; however, current therapies are frequently insufficient owing to severe side effects or limited effectiveness. Therefore, the discovery of new analgesics is needed, especially to treat the proportion of painful patients poorly improved by available analgesics. The transmission of nociceptive stimuli in primary afferent neurons critically depends on a peculiar repertoire of various types of ion channels such as a number of TRP channels, persistent sodium channels, inwardly rectifying potassium channels and voltage-gated calcium channels that either detect noxious stimuli, or regulate cellular excitability and synaptic transmission. Moreover, some of these channels are redistributed and upregulated in pathological states leading to abnormal detection or transmission of harmful stimuli, and consequently lead to states of chronic pain. Hence, these channels are considered key targets for the development of analgesics. The nervous system expresses multiple types of calcium channels with specialized roles in neurophysiology. Here, we review the role of these channels and their accessory subunits in nociceptive signaling, and their potential as targets for development of innovative analgesics.
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Role of Cation-Chloride-Cotransporters (CCC) in Pain and Hyperalgesia
Authors: Theodore J. Price, Fernando Cervero and Yves de KoninckThe importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. Here we review recent evidence that two cation-chloride cotransporters, NKCC1 and KCC2 are involved in pain and enhanced nociception. On the one hand, NKCC1 activity is upregulated in primary afferents following an inflammatory insult and this produces excessive GABAergic depolarization in primary afferents leading to cross excitation between low and high threshold afferents. On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
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Cellular Signalling Pathways of Spinal Pain Neuroplasticity as Targets for Analgesic Development
More LessNociceptive inputs from primary afferents are primarily mediated at fast glutamatergic synapses onto second order neurons in the dorsal horn of the spinal cord through activation of AMPA/kainate and NMDA receptor subtypes of ionotropic glutamate receptors. At these glutamatergic synapses several forms of short-lasting and long-lasting enhancement of synaptic transmission are known. Enhancement of excitatory synaptic transmission in nociceptive pathways is thought to be a key neural substrate underlying chronic pain, and thus the cellular and molecular mechanisms producing this enhancement represent potential targets for developing novel forms of therapeutics. Central to the mechanisms for pain hypersensitivity is the NMDA receptor, the activity of which is facilitated by convergent intracellular biochemical cascades in dorsal horn neurons. Cellular changes are not restricted to neurons in the dorsal horn, however, and there is growing evidence for involvement of glia, and of glia-neuronal signaling, in initiating and sustaining enhancement of nociceptive transmission. In particular, a role has emerged for microglia in pain hypersensitivity following nerve injury. This expanded understanding of cellular and molecular signalling mechanisms in the dorsal horn, that includes both neurons and glia, provides a basis of creating new types of strategies for management, and also for diagnosis, of chronic pain.
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Proteases and Protease-Activated Receptors (PARs): Novel Signals for Pain
Authors: N. Cenac and N. VergnolleThe recent detection of protease-activated receptors (PARs) on neurons of the peripheral and central nervous systems suggests that PARs and proteases that activate them, might be involved in neuronal functions. Among those functions, a particular focus on nociception has attracted considerable interest. The present article summarizes recent research progress on proteases and PARs as nociceptive signaling molecules in the nervous system and presents them as exciting new targets for therapeutic intervention in pain.
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New Approaches for the Treatment of Pain: The GDNF Family of Neurotrophic Growth Factors
Authors: Dinah W. Y. Sah, Michael H. Ossipov, Anthony Rossomando, Laura Silvian and Frank PorrecaThis article focuses on the GDNF family of neurotrophic factors as a potential new class of therapeutics for neuropathic pain, with a particular emphasis on the ligands, artemin and GDNF. In vivo activity of the ligands, expression of ligands and receptors after peripheral nerve injury, and modulation of nerve injury-induced changes by the ligands are reviewed in detail. Structural considerations, particularly with regard to implications for binding interactions and biological activity are discussed.
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Dynamic Medicinal Chemistry in the Elaboration of Morphine-6- Glucuronide Analogs
Authors: John R. Cashman and James M. MacDougallThis review discusses the role of dynamic medicinal chemistry in the design and development of more effective opioids for the treatment of pain. Human Phase II clinical studies have shown that morphine-6-glucuronide (M6G) has equivalent analgesic effects to morphine and an improved side effect profile particularly at reducing the tendency to cause nausea, vomiting, sedation and respiratory depression. Based on these clinical observations, a new class of pain medication could be developed. Despite the promise, M6G is not an ideal drug because bioavailability is low and hydrolysis occurs in the gut. The literature covered includes a comprehensive list of work that illustrates: (i) the role of drug metabolism and drug disposition concepts in M6G analog drug development, (ii) the use of dynamic medicinal chemistry in improving M6G pharmaceutical properties, and (iii) the role of drug metabolism in enhancing bioavailability of M6G. Using optimized dynamic medicinal chemistry procedures for drug design and development, understanding the use of drug development concepts in early drug development and applying new methods from other fields may help advance this field of drug development. This review summarizes studies that support the feasibility of elaborating longeracting, less expensive pain medications with possibly a safer profile of side effects. Development of new pain medications for cancer and other diseases based on M6G could provide novel agents that could balance optimal analgesia with a decreased occurrence of adverse side effects.
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Volumes & issues
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Volume 25 (2025)
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Volume (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)
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