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- Volume 9, Issue 4, 2009
Current Topics in Medicinal Chemistry - Volume 9, Issue 4, 2009
Volume 9, Issue 4, 2009
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Editorial [Hot Topic: The Medicinal Chemistry of Ion Channels and Their Relevance in Drug Discovery (Guest Editor: Minyong Li)]
By Minyong LiIn this issue of Current Topics in Medicinal Chemistry, we highlight several aspects of the medicinal chemistry of ion channels and their relevance in drug discovery by collecting comprehensive reviews from several experts working in this field. As pore-forming proteins that regulate ion transport across the membrane on the basis of concentration and electrochemical gradients, ion channels are ubiquitously distributed in the membranes throughout all mammalian cellular life. Since ion channels, such as calcium, potassium and sodium channels, play critical roles in various hereditary, neurological and cardiovascular diseases, they have attracted much attention and are among the most promising classes of targets for drug design and discovery. I would like to express my sincere appreciation to all the authors for their outstanding contributions. I also thank Dr. Allen Reitz, Editor-in-Chief, for inviting me to prepare this special issue of Current Topics in Medicinal Chemistry. Our hope is that this issue will be an informative contribution to the field and will represent a key reference work for those medicinal chemists involved in ion channels.
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Researches Toward Potassium Channels on Tumor Progressions
Authors: Zheng Shen, Qian Yang and Qidong YouAs trans-membrane proteins located in cytoplasm and organelle membrane, potassium (K+) channels are generally divided into four super-families: voltage-gated K+ channels (Kv), Ca2+-activated K+ channels (KCa), inwardly rectifying K+ channels (Kir) and two-pore domain K+ channels (K2P). Since dysfunctions of K+ channels would induce many diseases, various studies toward their functions in physiologic and pathologic process have been extensively launched. This review focuses on the recent advances of K+ channels in tumor progression, including the brief introduction of K+ channels, the role of K+ channels in tumor cells, the possible mechanism of action at cellular level, and the possible application of K+ channel modulators in cancer chemotherapy.
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The Interactions Between hERG Potassium Channel and Blockers
Authors: Lupei Du, Minyong Li and Qidong YouThe human ether-a-go-go related gene (hERG) potassium channel is critical to the QT interval in the human heart measured by the electrocardiogram (ECG). The blockade of hERG would induce undesired lethal arrhythmia, named torsades de pointes (TdP), a rare but life-threatening symptom. Although a large number of experimental studies on hERG have been conducted so far, knowledge of how known ligands bind to hERG still remains sketchy and has been a major hindrance in the effort to designing novel medicinal molecules devoid of hERG activity in the hope of improving drug safety. This review summarizes several studies on ligand-hERG interactions by in silico receptor-based and ligand-based modeling approaches during recent years. These efforts could aid tremendously in understanding the determinants of ligand binding to hERG channel and the molecular basis of hERG channel blockade, and offer a more rational approach for the prediction of QT-prolongation liability and for the development of novel and safe non-cardiac agents.
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Drug Discoveries Towards Kv1.5 Potassium Channel
Authors: Qian Yang, Xiaojian Wang, Lupei Du, Minyong Li and Qidong YouAttributed to the extensive researches towards the functions of Kv1.5 gene (also known as KCN5A gene), the therapeutic significances of Kv1.5 channel have been paid special attentions to cardiovascular diseases as well as tumor, the top two public-health problems for the aging population. During recent years, the hindrance for developing cardiovascular drugs is how to discriminate their therapeutic effect from cardiotoxicities. Therefore, targeting Kv1.5 gene, which encodes the atrial selective IKur potassium channel, has been confirmed as an appealing strategy for the treatment of atrial diseases. Moreover, the functions of Kv1.5 gene in carcinoma progression have also provoked a flurry of research in the hope of developing adjunctive or combined treatment of Kv1.5 modulators to enhance curative effects of classic chemotherapeutic agents.
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Current Strategies for the Discovery of K+ Channel Modulators
Authors: Deju Ye, Jiang Wang, Kunqian Yu, Yu Zhou, Hualiang Jiang, Kaixian Chen and Hong LiuPotassium ion (K+) channels consist of a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, such as the regulation of neuronal excitability, muscle contraction, cell proliferation, and insulin secretion. Due to their pivotal functions in biological systems, K+ channels have long been attractive targets for the rational drug design on the basis of their structures and interaction mechanisms. Various smallmolecular compounds and toxins have been discovered to act as K+ channel modulators. In the present review, we will first briefly discuss current knowledge of the structures and functions of K+ channels, and then review the recent strategies for the discovery of K+ channel modulators, focusing especially on the virtual screening approaches and chemical synthesis technologies.
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Voltage-Gated Sodium Channel Blockers for the Treatment of Chronic Pain
Authors: Mark A. Matulenko, Marc J. C. Scanio and Michael E. KortThe voltage-gated sodium channels are a family of proteins that control the flow of sodium ions across cell membranes. Considerable data support the hypothesis that hyperexcitability and spontaneous action potential firing in peripheral sensory neurons mediated by voltage-gated sodium channels contribute to the pathophysiology of chronic pain. Sodium channel blockers are, therefore, appealing entities for therapeutic intervention in painful human neuropathies. This review will focus on the latest advances in the development of small molecule sodium channel blockers and their application to the treatment of chronic pain.
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Recent Updates of N-Type Calcium Channel Blockers with Therapeutic Potential for Neuropathic Pain and Stroke
Authors: Takashi Yamamoto and Akira TakaharaThe voltage-dependent N-type calcium channel (Cav2.2), which is distributed in the nerve endings of the central and peripheral nerves, is known to be strongly associated with the pathological processes of cerebral ischemia and neuropathic pain. Ziconotide, the chemically synthesized version of the 25-residue peptide marine toxin ω-conotoxin MVIIA, has been approved as an analgesic drug for severe chronic pain treatment. A blockade of N-type calcium channels has been suggested for reducing the neuronal injury occurring from ischemia/reperfusion events. Therefore, many efforts have been made to develop systemically available small-molecule N-type calcium channel blockers thus far. This review focuses on the latest updates concerning small-molecule N-type calcium channel blockers as potential candidates for the next generation of therapeutics for neuropathic pain and ischemic stroke. The pharmacological advantages of N-type calcium channel blockers in these pathological states are also described.
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Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential
Authors: Valentina Zuliani, Manoj K. Patel, Marco Fantini and Mirko RivaraThe voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability. Abnormal activity of sodium channels is related to several pathological processes, including cardiac arrhythmias, epilepsy, chronic pain, neurodegenerative diseases and spasticity. In view of this, VGSCs are considered important therapeutic targets for the treatment of these disorders. To date, nine VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSCs also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective antagonists, but also antagonists that exhibit state selectivity, particularly to the inactivated state of the channel. This review will provide a brief historical prospective and will primarily focus on recent advances in the development of isoform specific and state selective sodium channel antagonists and the medicinal chemistry involved, surveying the emerging therapeutic fields.
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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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