Nereistoxin is a

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

identified in 1962 as the toxic

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

''N'',''N''-dimethyl-1,2-dithiolan-4-amine. It had first been isolated in 1934 from the marine

annelid The annelids (Annelida , from Latin ', "little ring"), also known as the segmented worms, are a large phylum, with over 22,000 extant species including ragworms, earthworms, and leeches. The species exist in and have adapted to various ecol ...

''Lumbriconereis heteropoda'' and acts by blocking the

nicotinic acetylcholine receptor 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 ne ...

. Researchers at

Takeda is a Japanese family name.1990 Census Name Files

in Japan investigated it as a possible

insecticide Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...

. They subsequently developed a number of derivatives that were commercialised, including those with the

ISO ISO is the most common abbreviation for the International Organization for Standardization. ISO or Iso may also refer to: Business and finance * Iso (supermarket), a chain of Danish supermarkets incorporated into the SuperBest chain in 2007 * Iso ...

common names In biology, a common name of a taxon or organism (also known as a vernacular name, English name, colloquial name, country name, popular name, or farmer's name) is a name that is based on the normal language of everyday life; and is often contrast ...

bensultap, cartap, thiocyclam and thiosultap.

Structures and synthesis

Bensultap.svg, bensultap Thiocyclam neutral.svg, thiocyclam Thiosultap.svg, thiosultap Bensultap (R=SO₂Ph) was made by the reaction of the sodium salt of benzenethiolsulfonate (PhSO₂SNa) with ''N'',''N''-dimethyl 1,3-dichloro-2-propylamine or ''N'',''N''-dimethyl 2,3-dichloropropylamine in ethanol. : Bensultap synthesis

Bensultap can be converted to nereistoxin by treatment with

alkali In chemistry, an alkali (; from ar, القلوي, al-qaly, lit=ashes of the saltwort) is a basic, ionic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of a ...

History

Japanese fishermen used the annelid worm ''Lumbriconereis heteropoda'' Marenz as bait and after accidental poisonings the chemical agent responsible was identified and named nereistoxin. In the 1960s, researchers at Takeda Chemical Industries synthesised the active material ''N'',''N''-dimethyl-1,2-dithiolan-4-amine and derivatives in which the sulfur-sulfur bond of the

dithiolane A dithiolane is a sulfur heterocyclic compound, heterocycle derived from cyclopentane by replacing two methylene bridges (-- units) with thioether groups. The parent compounds are 1,2-dithiolane and 1,3-dithiolane. 1,2-Dithiolanes are cyclic disu ...

ring was replaced by alternative sulfur-linked groups. The resulting compounds were in many cases less toxic to mammals than the natural product while retaining good activity on insects. It was subsequently shown that all the compounds which were commercialised acted by being propesticides — breaking down in the environment to nereistoxin or its uncyclised dithiol.

Mechanism of action

Nereistoxin has chemical similarity to

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

and its mode of action was suggested originally as being possibly by interference with

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

. Later

electrophysiological Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , ''-logia'') is the branch of physiology that studies the electrical properties of bi ...

studies using

synapses In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

from the cockroach ''

Periplaneta americana The american cockroach (''Periplaneta americana'') is the largest species of common cockroach, and often considered a pest. In certain regions of the U.S. it is colloquially known as the waterbug, though it is not a true waterbug since it is not ...

'' showed that it acts by blocking the nicotinic acetylcholine receptor / ion channel complex in the insect central nervous system. This is also the mode of action of the related insecticides, all of which can produce the dithiol corresponding to cleavage of the 1,2-thiolane ring in the parent compound.

Usage

None of the insecticidal analogues of nereistoxin became major products in agriculture and their use was mainly limited to Japanese and Chinese cultivation of rice, where their control of pests such as the rice stem borer '' Chilo suppressalis'' was significant. They were not licensed for use in Europe or the USA. The limited success of this group of chemicals was partly due to other compounds having similar modes of action but higher potency and mammalian safety becoming available.

References

External links