Surugatoxin

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Surugatoxin
Surugatoxin.svg
Identifiers
  • [(3S)-2,3,4,5,6-pentahydroxycyclohexyl] (6aS,8R,9S,11aS)-6'-bromo-6a,9-dihydroxy-9-methyl-1,2',3,10-tetraoxo-spiro[4,6,7,11a-tetrahydropyrido[1,2-f]pteridine-8,3'-indoline]-7-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H26BrN5O13
Molar mass 684.409 g·mol−1
3D model (JSmol)
  • CC1(C(=O)N2C3=C(NCC2(C(C14C5=C(C=C(C=C5)Br)NC4=O)C(=O)OC6C(C(C(C(C6O)O)O)O)O)O)NC(=O)NC3=O)O

Surugatoxin (SGTX) is a type of venom found in the mid-gut digestive gland of the Japanese ivory mollusk Babylonia japonica, a carnivorous gastropod. [1] It functions as a ganglionic blocker of nicotinic acetylcholine receptors (nAChRs). [1] The structurally and functionally related neosurugatoxin, also derived from Babylonia japonica, is an even more potent nAChR antagonist than SGTX. [2]

Contents

SGTX is a colorless crystalline substance with the chemical formula C25H26BrN5O13 and a molecular weight of 684.4g/mol. Its systematic chemical name is [(2R,3S,5S,6S)-2,3,4,5,6-pentahydroxycyclohexyl] (6aS,7R,8R,9R)-6'-bromo-6a,9-dihydroxy-9-methyl-1,2',3,10-tetraoxo-spiro[4,5,6,7-tetrahydropyrido[1,2-f]pteridine-8,3'-indoline]-7-carboxylate. [3] It is insoluble in organic solvents and has very low solubility in water. [4]

The ganglionic blockade of nAChRs by SGTX is similar to that of IS-toxin, a structurally similar compound derived from the same mollusk, Babylonia japonica. [1] [5]

Background and discovery

A food poisoning outbreak of 26 cases in the Ganyudo area of Suruga Bay, Shizuoka Prefecture in Japan in September 1965 was traced to ingestion of the toxin surugatoxin (SGTX), named for Suruga Bay. [6] SGTX is contained in the mid-gut digestive gland of the Japanese ivory mollusk, Babylonia japonica, which is used as an ingredient in sushi and sashimi. [1] The food-poisoning patients reported a variety of symptoms, including visual disorders, speech disorders, lazy eye amblyopia, pupil dilation (mydriasis), abdominal distention, dry mouth, numbness of lips, constipation, and vomiting. [1] [6]

The toxicity shellfish from the Suruga Bay area varied with time – the toxicity was only present during July through September, when temperatures sometimes reached 25°C and it rapidly declined after 1978, making the availability of surugatoxin and the related substances neosurugatoxin and prosurugatoxin unavailable for research. Kosuge and colleagues [7] found that these toxins are actually the metabolized products of a marine bacterium that belongs to the Coryneform group. Toxicity is a result of bioaccumulation.

Behavioral and physiological effects

A number of researchers have characterized the effect of surugatoxin on behavior and physiology in animal models [1] [4]

Mice

SGTX causes disturbances in gait, suppression of spontaneous motility, and mydriasis in mice at intravenous (i.v.) dose levels of 0.5-1.0 mg/kg. [4] At higher doses (20–40 mg/kg), intraperitoneal (i.p.) application of SGTX caused depression of respiratory movement and tremor.

Rats

SGTX blocks orthodromic transmission, as evidenced by the fact that the synaptic potential is strongly depressed with application of the toxin and the block intensifies as stimulus frequency increases. [8] This effect is slow to develop and is similar to another ganglionic nACHR antagonist, hexamethonium.

Cats

SGTX causes depression of spontaneous movement, mydriasis, and relaxation of the nictitating membrane in cats at i.v. dose levels of 0.15-0.2 mg/kg. Further, it produces hypotension of 1–2 hours in duration that is not prevented by treatment with atropine or propranolol. [1]

Humans

Most clinical symptoms resulting from Babylonia japonica ingestion, as in the 1965 food-poisoning outbreak, seem to be mediated by ganglion-blockade of nicotinic ACh receptors at various sites; visual impairments and mydriasis due to ciliary ganglion blockade, dry mouth due to submaxillary and otic ganglion blockade, and constipation and abdominal distention due to intestinal intrinsic nerve blockade. [1]

Pharmacology

Surugatoxin is a specific, reversible, competitive antagonist of ganglionic nicotinic acetylcholine receptors (nACHRs). [9] Although a number of articles were published in the two decades following the discovery of SGTX in the mid-1960s, relatively little is known about the pharmacological properties of this toxin. Ascher and colleagues [9] posit that ganglionic blockade by SGTX results from binding to the closed state of the channel-receptor complex, possibly to the receptor itself. It is 50-100 times more potent than hexamethonium, another ganglionic antagonist of nAChRs. [1] Brown and colleagues found that the SGTX dissociation constants measured at equilibrium block in rats were 58nM and 76nM, as measured from the shift in depolarization produced by 0.2μM and 2 μM SGTX, respectively. [8] Surugatoxin is listed on two U.S. patents, both for potential clinical treatments. US7468188 [10] proposes the use of locally-administered neurotoxins in the treatment of muscle injury and US7214700 [11] proposes the use of (2-Oxindol-3-ylidenyl) acetic acid derivatives as protein kinase inhibitors. Surugatoxin has not been demonstrated to be effective in either of these treatment proposals, but rather, is listed as a potentially relevant substance in these treatment plans.

Related Research Articles

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An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">Muscarinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of muscarine

Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.

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<span class="mw-page-title-main">Hexamethonium</span> Chemical compound

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α-Bungarotoxin Chemical compound

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<span class="mw-page-title-main">Cobratoxin</span> Chemical compound

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References

  1. 1 2 3 4 5 6 7 8 9 Hayashi E, Yamada S (February 1975). "Pharmacological studies on surugatoxin, the toxic principle from Japanese ivory mollusc (Babylonia japonica)". British Journal of Pharmacology. 53 (2): 207–215. doi:10.1111/j.1476-5381.1975.tb07350.x. PMC   1666298 . PMID   238699.
  2. Fusetani N, Kem W (2009). "Marine toxins: an overview". Marine Toxins as Research Tools. Progress in Molecular and Subcellular Biology. Vol. 46. pp. 1–44. Bibcode:2009mtrt.book....1F. doi:10.1007/978-3-540-87895-7_1. ISBN   978-3-540-87892-6. PMID   19184583.
  3. "Surugatoxin". ChemSpider. Retrieved 14 May 2012.
  4. 1 2 3 Hirayama H, Sugihara K, Tsuyama S, Wakigawa K, Okuma H (August 1974). "A ganglion blocking action of toxic substances, IS-toxin and surugatoxin, from the Japanese ivory shell, Babylonia japonica". Japanese Journal of Pharmacology. 24 (4): 559–574. doi: 10.1254/jjp.24.559 . PMID   4156375.
  5. Hirayama H, Gogi K, Urakawa N, Ikeda M (June 1970). "A ganglion-blocking action of the toxin isolated from Japanese ivory shell (Babylonia japonica)". Japanese Journal of Pharmacology. 20 (2): 311–312. doi: 10.1254/jjp.20.311 . PMID   4393951.
  6. 1 2 Kosuge T, Tsuji K, Hirai K (September 1982). "Isolation of neosurugatoxin from the Japanese ivory shell, Babylonia japonica". Chemical & Pharmaceutical Bulletin. 30 (9): 3255–3259. doi:10.1248/cpb.30.3255. PMID   7172333.
  7. Kosuge T, Tsuji K, Hirai K, Fukuyama T (July 1985). "First evidence of toxin production by bacteria in a marine organism". Chemical & Pharmaceutical Bulletin. 33 (7): 3059–3061. doi: 10.1248/cpb.33.3059 . PMID   2867831.
  8. 1 2 Brown DA, Garthwaite J (September 1976). "Action of surugatoxin on nicotinic receptors in the superior cervical ganglion of the rat". British Journal of Pharmacology. 58 (1): 157–159. doi:10.1111/j.1476-5381.1976.tb07705.x. PMC   1667125 . PMID   974373.
  9. 1 2 Ascher P, Large WA, Rang HP (October 1979). "Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells". The Journal of Physiology. 295: 139–170. doi:10.1113/jphysiol.1979.sp012958. PMC   1278790 . PMID   42780.
  10. US 7468188,Brooks GF, Aoki KR,"Multi-step therapy for injured muscles",issued 23 December 2008, assigned to Allergan Inc
  11. US 7214700,Wei CC, Tang PC,"(2-Oxindol-3-ylidenyl) acetic acid derivatives and their use as protein kinase inhibitors",issued 8 May 2007, assigned to Sugen LLC