Marine Drugs

Review

19 pages, 210 KB

Open AccessReview

The Nemertine Toxin Anabaseine and Its Derivative DMXBA (GTS-21): Chemical and Pharmacological Properties

by William Kem, Ferenc Soti, Kristin Wildeboer, Susan LeFrancois, Kelly MacDougall, Dong-Qing Wei, Kuo-Chen Chou and Hugo R. Arias

Mar. Drugs 2006, 4(3), 255-273; https://doi.org/10.3390/md403255 - 6 Apr 2006

Cited by 65 | Viewed by 17613

Abstract

Nemertines are a phylum of carnivorous marine worms that possess a variety of alkaloidal, peptidic or proteinaceous toxins that serve as chemical defenses against potential predators. The hoplonemertines additionally envenomate their prey with a mixture of proboscis alkaloids delivered with the help of [...] Read more.

Nemertines are a phylum of carnivorous marine worms that possess a variety of alkaloidal, peptidic or proteinaceous toxins that serve as chemical defenses against potential predators. The hoplonemertines additionally envenomate their prey with a mixture of proboscis alkaloids delivered with the help of a calcareous stylet that punctures the skin of the victim. Anabaseine, the first of these alkaloids to be identified, stimulates a wide variety of animal nicotinic acetylcholine receptors (AChRs), especially the neuromuscular [e.g., α1₂β1γδ (embryogenic) or α1₂β1γε (adult)] and α7 AChRs that are inhibited by the snake peptide α-bungarotoxin. A synthetic derivative, 3-(2,4-Dimethoxybenzylidene)-Anabaseine (DMXBA; also called GTS-21), improves memory in experimental animals and humans and is currently in clinical trials to determine whether it can ameliorate cognitive problems associated with schizophrenia. Here we summarize present knowledge concerning the chemistry and mechanisms of action of these two substances (anabaseine and DMXBA) on AChRs, especially those found in the mammalian brain. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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27 pages, 186 KB

Open AccessReview

The Chemistry and Pharmacology of Anatoxin-a and Related Homotropanes with respect to Nicotinic Acetylcholine Receptors

by Susan Wonnacott and Timothy Gallagher

Mar. Drugs 2006, 4(3), 228-254; https://doi.org/10.3390/md403228 - 6 Apr 2006

Cited by 72 | Viewed by 14621

Abstract

This chapter covers the chemistry and nicotinic pharmacology of naturally occurring homotropane alkaloids, with an emphasis of anatoxin-a. In addition to anatoxin-a, homoanatoxin and pinnamine, as well as the major classes of synthetic derivatives of anatoxin-a including UB-165, are discussed. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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13 pages, 232 KB

Open AccessReview

New Conotoxin SO-3 Targeting N-type Voltage-Sensitive Calcium Channels

by Lei Wen, Sheng Yang, Wenxia Zhou, Yongxiang Zhang and Peitang Huang

Mar. Drugs 2006, 4(3), 215-227; https://doi.org/10.3390/md403215 - 6 Apr 2006

Cited by 8 | Viewed by 10703

Abstract

Selective blockers of the N-type voltage-sensitive calcium (CaV) channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from [...] Read more.

Selective blockers of the N-type voltage-sensitive calcium (CaV) channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from the venom of Conus striatus, and contains the same 4-loop, 6-cysteine framework (C-C-CC-C-C) as O-superfamily conotoxins. The synthetic SO-3 has high analgesic activity similar to ω-conotoxin MVIIA (MVIIA), a selective N-type CaV channel blocker approved in the USA and Europe for the alleviation of persistent pain states. In electrophysiological studies, SO-3 shows more selectivity towards the N-type CaV channels than MVIIA. The dissimilarity between SO-3 and MVIIA in the primary and tertiary structures is further discussed in an attempt to illustrate the difference in selectivity of SO-3 and MVIIA towards N-type CaV channels. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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22 pages, 419 KB

Open AccessReview

ω-Conotoxins GVIA, MVIIA and CVID: SAR and Clinical Potential

by Christina I. Schroeder and Richard J. Lewis

Mar. Drugs 2006, 4(3), 193-214; https://doi.org/10.3390/md403193 - 6 Apr 2006

Cited by 30 | Viewed by 16985

Abstract

Highly selective N-type voltage-gated calcium (CaV) channel inhibitors from cone snail venom (the ω-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt (Elan) or synthetic ω-conotoxin MVIIA, was the first ω-conotoxin [...] Read more.

Highly selective N-type voltage-gated calcium (CaV) channel inhibitors from cone snail venom (the ω-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt (Elan) or synthetic ω-conotoxin MVIIA, was the first ω-conotoxin to be approved by Food and Drug Administration for human use. This review compares the action of three ω-conotoxins, GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved N-type therapeutics that are more useful in the treatment of chronic pain. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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36 pages, 925 KB

Open AccessReview

Marine Toxins That Target Voltage-gated Sodium Channels

by Ahmed Al-Sabi, Jeff McArthur, Vitaly Ostroumov and Robert J. French

Mar. Drugs 2006, 4(3), 157-192; https://doi.org/10.3390/md403157 - 6 Apr 2006

Cited by 63 | Viewed by 16693

Abstract

Eukaryotic, voltage-gated sodium (Na_V) channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different NaV receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and [...] Read more.

Eukaryotic, voltage-gated sodium (Na_V) channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different NaV receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and site-directed mutagenesis. In the marine ecosystem, numerous toxins have evolved to disrupt NaV channel function, either by inhibition of current flow through the channels, or by modifying the activation and inactivation gating processes by which the channels open and close. These toxins function in their native environment as offensive or defensive weapons in prey capture or deterrence of predators. In composition, they range from organic molecules of varying size and complexity to peptides consisting of ~10-70 amino acids. We review the variety of known Na_V-targeted marine toxins, outlining, where known, their sites of interaction with the channel protein and their functional effects. In a number of cases, these natural ligands have the potential applications as drugs in clinical settings, or as models for drug development. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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14 pages, 90 KB

Open AccessReview

The Structural Basis and Functional Consequences of Interactions Between Tetrodotoxin and Voltage-Gated Sodium Channels

by Shana L. Geffeney and C. Ruben

Mar. Drugs 2006, 4(3), 143-156; https://doi.org/10.3390/md403143 - 6 Apr 2006

Cited by 21 | Viewed by 13380

Abstract

Tetrodotoxin (TTX) is a highly specific blocker of voltage-gated sodium channels. The dissociation constant of block varies with different channel isoforms. Until recently, channel resistance was thought to be primarily imparted by amino acid substitutions at a single position in domain I. Recent [...] Read more.

Tetrodotoxin (TTX) is a highly specific blocker of voltage-gated sodium channels. The dissociation constant of block varies with different channel isoforms. Until recently, channel resistance was thought to be primarily imparted by amino acid substitutions at a single position in domain I. Recent work reveals a novel site for tetrodotoxin resistance in the P-region of domain IV. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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24 pages, 125 KB

Open AccessReview

Conotoxins: Therapeutic Potential and Application

by Richard T. Layer and J. Michael McIntosh

Mar. Drugs 2006, 4(3), 119-142; https://doi.org/10.3390/md403119 - 6 Apr 2006

Cited by 56 | Viewed by 14328

Abstract

The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target [...] Read more.

The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target receptors and ion channels of excitable tissues, such as ligandgated nicotinic acetylcholine, N-methyl-D-aspartate, and type 3 serotonin receptors, as well as voltage-gated calcium, sodium, and potassium channels, and G-protein-coupled receptors including α-adrenergic, neurotensin, and vasopressin receptors, and the norepinephrine transporter. Several conotoxins have shown promise in preclinical models of pain, convulsive disorders, stroke, neuromuscular block, and cardioprotection. The pharmacological selectivity of the conotoxins, coupled with the safety and efficacy demonstrated in preclinical models, has led to their investigation as human therapeutic agents. In the following review, we will survey the pharmacology and therapeutic rationale of those conotoxins with potential clinical application, and discuss the unique challenges that each will face in the course of their transition from venom component to human therapeutic. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

37 pages, 502 KB

Open AccessReview

Ciguatoxins: Cyclic Polyether Modulators of Voltage-gated Iion Channel Function

by Graham M. Nicholson and Richard J. Lewis

Mar. Drugs 2006, 4(3), 82-118; https://doi.org/10.3390/md403082 - 6 Apr 2006

Cited by 114 | Viewed by 20678

Abstract

Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins [...] Read more.

Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na⁺-dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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12 pages, 97 KB

Open AccessReview

Cnidarian Toxins Acting on Voltage-Gated Ion Channels

by Shanta M. Messerli and Robert M. Greenberg

Mar. Drugs 2006, 4(3), 70-81; https://doi.org/10.3390/md403070 - 6 Apr 2006

Cited by 24 | Viewed by 11732

Abstract

Voltage-gated ion channels generate electrical activity in excitable cells. As such, they are essential components of neuromuscular and neuronal systems, and are targeted by toxins from a wide variety of phyla, including the cnidarians. Here, we review cnidarian toxins known to target voltage-gated [...] Read more.

Voltage-gated ion channels generate electrical activity in excitable cells. As such, they are essential components of neuromuscular and neuronal systems, and are targeted by toxins from a wide variety of phyla, including the cnidarians. Here, we review cnidarian toxins known to target voltage-gated ion channels, the specific channel types targeted, and, where known, the sites of action of cnidarian toxins on different channels. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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33 pages, 360 KB

Open AccessReview

Marine Toxins Targeting Ion Channels

by Hugo R. Arias

Mar. Drugs 2006, 4(3), 37-69; https://doi.org/10.3390/md403037 - 6 Apr 2006

Cited by 25 | Viewed by 18965

Abstract

This introductory minireview points out the importance of ion channels for cell communication. The basic concepts on the structure and function of ion channels triggered by membrane voltage changes, the so-called voltage-gated ion channels (VGIC_s), as well as those activated by [...] Read more.

This introductory minireview points out the importance of ion channels for cell communication. The basic concepts on the structure and function of ion channels triggered by membrane voltage changes, the so-called voltage-gated ion channels (VGIC_s), as well as those activated by neurotransmitters, the so-called ligand-gated ion channel (LGIC_s), are introduced. Among the most important VGIC superfamiles, we can name the voltage-gated Na⁺ (Na_V), Ca²⁺ (Ca_V), and K⁺ (K_V) channels. Among the most important LGIC super families, we can include the Cys-loop or nicotinicoid, the glutamate-activated (GluR), and the ATP-activated (P2X_nR) receptor superfamilies. Ion channels are transmembrane proteins that allow the passage of different ions in a specific or unspecific manner. For instance, the activation of Na_V, Ca_V, or K_V channels opens a pore that is specific for Na⁺, Ca²⁺, or K⁺, respectively. On the other hand, the activation of certain LGICs such as nicotinic acetylcholine receptors, GluRs, and P2XnRs allows the passage of cations (e.g., Na⁺, K⁺, and/or Ca²⁺), whereas the activation of other LGICs such as type A γ-butyric acid and glycine receptors allows the passage of anions (e.g., Cl⁻ and/or HCO₃⁻). In this regard, the activation of Na_V and Ca_V as well as ligand-gated cation channels produce membrane depolarization, which finally leads to stimulatory effects in the cell, whereas the activation of K_V as well as ligand-gated anion channels induce membrane hyperpolarization that finally leads to inhibitory effects in the cell. The importance of these ion channel superfamilies is emphasized by considering their physiological functions throughout the body as well as their pathophysiological implicance in several neuronal diseases. In this regard, natural molecules, and especially marine toxins, can be potentially used as modulators (e.g., inhibitors or prolongers) of ion channel functions to treat or to alleviate a specific ion channel-linked disease (e.g., channelopaties). Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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