Bufotenin structure

So much for the politics, and for the medical ethics lecture. What can one say about the drug itself This is an example of a very rare breed of active compounds, one that can be found in both the animal and the vegetable kingdoms. From toads to toadstools. There are a number of extremely close structural relatives out there in the wild world. Bufotenine must first and foremost be seen as an extremely close relative to serotonin (one of our principal neurotransmitter) of which it is the N,N-dimethyl homologue). There are many modifications of it in nature (found most frequently in the skins of frogs), and these all have deceptively similar names. It is helpful to me to tally them. 

This compound cluster exhibits a two-ring, "open-chained, indolic chemical structure, and in contrast to other psychedelics it is all but inactive when taken orally unless accompanied by certain other compounds. Shortacting tryptamines are closely related to neurotransmitters (such as bufotenine), to MDA (a major botanical source of the snuffs belongs to the nutmeg family), to tryptophan (an essential amino acid produced in human digestion of proteins) and to psilocybin and psilocin (which are tryptamines of longer duration). DMT, the simplest member, occurs normally in the blood, brain and (in higher concentrations) in the cerebrospinal fluid. 

The synthesis of bufotenine itself followed closely upon the proof of its structure. Hoshino and Shimodaira reduced the ethyl ester of 5-ethoxy-indole-3-acetic acid by the Bouveault-Blanc procedure to the corresponding primary alcohol, which was treated with phosphorus tribromide and then dimethylamine, to give the ethyl ether of bufotenine, which was demethylated with aluminum chloride (130). In a later synthesis, 2,5-dimethoxybenzyl cyanide (XXIII) was alkylated by Eisleb s method with dimethylaminoethyl chloride in the presence of sodamide to give l-(2,5-dimethoxyphenyl)-3-dimethylaminopropyl cyanide (XXIV), which was then hydrogenated over Haney nickel to yield 2-(2,5-di-methoxyphenyl)-4-dimethylaminobutylamine (XXV R = Me). De-methylation of this with hydrobromic acid, followed by oxidation of the product (XXV R = H) with potassium ferricyanide yielded bufotenine (XIX) via the related quinone (109). 

Noting the structural resemblance of serotonin to the hallucinogenic indoles dimethyl tryptamine (DMT) and bufotenin, researchers proposed that psychotic symptoms were caused by these or similar compounds generated in schizophrenics by the abnormal transmethylation of endogenous indoleamines (21). Unfortunately, studies were unable to confirm increases in methylated indole amines in the plasma or CSF of schizophrenic patients versus controls (22). The transmethylation hypothesis is also questioned by the recognition that LSD-induced psychosis differs significant ways from the signs and symptoms of schizophrenia (23). 

The structural similarity between 5-HT, and nACh receptors provides for an interesting but complex pharmacological overlap (Table 14.13). An overlap of agonist activity is known with N-methyl bufotenine iodide [the quaternary salt of serotonin 5-HT = 75... 

Wieland and co-workers (913) in 1931 isolated from the skin secretion of the toad two indole derivatives, bufotenin and bufotenidin, whose correct structure (diagram 24) was established soon after (914) and confirmed by synthesis (416, cf. 363). Dehydrobufotenin was isolated in 1935 (443) and the previously isolated bufothionin (915) shown to be its sulfate ester (916, cf. diagram 24). 

A number of psychotomimetic substances—including adrenochrome and adrenolutin which are derived from adrenaline —are indole compounds and are therefore structurally related to 5-hydroxytryptamine. The most extensively studied member of the group—LSD25—is, however, less closely related to 5-hydroxytryptamine than are compounds such as bufotenine. 

Toad extract, obtained from the secretions of the salivary and skin glands of Chinese toads, is commonly used in Chinese medicine. It contains bufotenine and a series of bufadienolides that are structurally similar to cardiac glycosides [119 ]. 

When Wieland et al. (1934) and Jensen and Chen (1936) isolated bufotenine (iV,N-dimethyl-5-hydroxytryptamine) and related indoleamines from the toad venom gland, they considered them as poisons peculiar to this species of animal. About twenty years elapsed before Rapport et al. (1948) isolated serotonin (5-hydroxytryptamine) from beef blood and determined its structure (Rapport, 1949). With the isolation of serotonin the full significance of the indoleamines in nature began to unfold. 

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