Phenylethylamines mescaline

Seven groups of these drugs can be separated based on their various chemical f structures (a) lysergic acid derivatives, of which lysergide (LSD) is the prototype (b) phenylethylamine derivatives, of which 3,4,5-trihydroxyphenylethylamine (mescaline) is the prototype (c) indolealkylamines, such as 4-phosphorodi-methyltryptamine (psilocybin) (d) other indolic derivatives, such as the harmine... 

While the majority of studies have focused on LSD, some evidence suggests that hallucinogens derived from the phenylethylamine nucleus affect locomotion in a manner that is interpretable only by considering the environmental context. For example, the substituted amphetamine DOM produces a dose-dependent (0.5-10 mg/kg) reduction in locomotor activity when rats are tested in a novel open field, while a slight but significant increase in activity is observed in a familiar environment (171). This report corroborates the separate findings of DOM-induced hyperactivity in rats or mice in a familiar chamber (29,196) and hypoactivity in mice in an unfamiliar setting (92). Mescaline (10 mg/kg) has also been reported to increase locomotion in rats in a familiar environment (196). 

A number of very important natural and synthetic biochemicals belong to the phenylethylamine family. Two of these compounds, dopamine and epinephrine (adrenaline), are neurotransmitters, substances that carry chemical messages through the nervous system of humans and other animals. A third phenylethylamine, tyrosine, is an essential amino acid. And a familiar phenylethylamine found in plants is mescaline, whose chemical name is 2-(3,4,5-trimethoxy-phenyl)ethylamine. The primary natural sources of mescaline are four varieties of cactus two peyote species (Lophophora wiUiamsii and Lophophora diffusa), the San Pedro cactus (Trichocereus pacha-noi), and the Peruvian Torch cactus (Trichocereus peruvianus). 

The hallucinogens generally fall into two chemical classes. The indole alkylamines include LSD, psilocybin, psilocin, dimethyltryptamine (DMT), and diethyltrypta-mine (DET), all of which are structurally similar to serotonin. The other chemical subclass of hallucinogens contains phenylethylamine derivatives such as mescaline, MDMA, MDA, and DOM (dimethoxymethyl amphetamine). A related stimulatory hallucinogen, PCP, is a piperidine analogue that produces unique effects. 

Mescaline (=Mezcaline 3,4,5-Trimethoxy-phenethylamine) (phenylethylamine) A-Methylmescaline (= A -Methylmezcaline 7 1Methyl-3,4,5-trimethoxy-phenethylamine) (phenylethylamine) Procyanidin B2 (= Epicatechin (4(3 —>8) epicatechin) (procyanidin dimer) Procyanidin B3 (= Catechin (4a—>8) catechin (procyanidin dimer)... 

Biologically active derivatives of 2-phenylethylamine—adrenaline, noradrenaline, methamphetamine, mescaline, dopamine, fentanyl (a synthetic narcotic), and sumatriptan (Imitrex, a synthetic pain reliever) (Section 25.6C)... 

Aromatic amino acids that originate from the shikimate pathway also act as precursors to many alkaloids. Alkaloids that contain a phenylethylamine moiety are derived from L-tyrosine or its oxidation product L-dihydroxyphenylalanine (L-DOPA). Mescaline (N7) originating from the latter amino acid is known to occur in several cacti and is responsible for the hallucinogenic activity of peyote (Lophophora williamsii, Cactaceae). Lophocerine is a tetrahydroisoquinoline alkaloid derived from L-dopamine and found to occur in a different Lophophora species, L. schotti. 

It is known that the natural base mescaline (trimethoxy-phenylethylamine) which occurs in various kinds of anhalonium can be made synthetically by reducing 3,4,5-trimethoxynitrostyrene. It has now been found that in the same way there can be obtained the hitherto unknown 0-homologues of this compound, which also have valuable therapeutic properties and, moreover may be used as parent materials for the manufacture of medicinal products. 

Thus 3,4,5-triethoxy-phenylethylamine is obtained by reducing 3,4,5-triethoxynitrostyrene, for instance by treatment with a catalyst and hydrogen or by electrolysis. The compound thus obtained has properties similar to those of mescaline. It is, however, active even in essentially smaller doses. 

MMDA (methoxymethylenedioxyamphetamine) is a phenylethylamine compound structurally related to amphetamine and mescaline. It is a potent psychotropic (hallucinogenic) but is not used in therapeutics. It is a drug of abuse. 

At least eighteen phenylethylamines have been examined by x-ray crystallography. Among these are phenylethylamine hydrochloride (3 ), ephedrine hydrochloride (31), ephedrine monohydrogen phosphate monohydrate (32), ephedrine dihydrogen phosphate (33), dopamine hydrochloride (34), 5-hydroxydopamine hydrochloride (35), 6-hydroxydopamine hydrochloride (36), epinephrine hydrogen tartrate (37), norepinephrine hydrochloride (38), isoproterenol sulfate (39), 2,4,5-trimethoxyamphetamine hydrochloride (40), 4-ethyl-2,5-dimethoxyamphetamine (41), mescaline hydrobromide (42), and mescaline hydrochloride (43). 

The difficulties which may be encountered in establishing well-known pathways in a new plant are illustrated by feeding experiments with [2 - " C]tyrosine, [l, 2 - H2]dopamine, and 3-hydroxy-4-methoxy[ar- H]phenylethylamine in E. merkei The conversion of tyrosine into hordenine (63), established in barley could not be demonstrated. Nor were tyrosine and dopamine incorporated into salsoline (55), but all three of the labelled compounds were converted into 3,4-dimethoxyphenylethylamine. These results were rationalized as indicating a pathway that diverged after dopamine with appropriate methylation, giving either salsoline (55) or 3,4-dimethoxyphenylethylamine (a similar branch point is observed in L. williamsii for the biosynthesis of mescaline and tetrahydroiso-quinolines). Further, at the time of the experiments the required methyl-transferases for salsoline and hordenine biosynthesis were apparently blocked. In any event the pathway to 3,4-dimethoxyphenylethylamine is manifestly the dominant one, as this alkaloid and its iV-methyl derivatives are major constituent bases of this plant. 

An 0-methyltransferase has been isolated from L. williamsii, which in conjunction with S-adenosyl-L-methionine will effect methylation of various hydroxy-lated phenylethylamines. Methylation of dopamine gave a single monomethyl compound, the mescaline precursor 4-hydroxy-3-methoxyphenylethylamine (64) which, satisfyingly, was methylated twice as fast as 3-hydroxy-4-methoxy-phenylethylamine to give the naturally occurring 3,4-dimethoxyphenylethylamine. 

In these amphetamine derivatives, the hallucinogenic effects are predominant, exceeding those of the phenylethylamines many times over. Thus, for example, 2,5-dimethoxy-4-methylamphetamine (DOM) has approximately 100 times the effect of mescalin [11]. Its effects of serenity, tranquility, and peace give the product its scene name STP . All substances, including 3,4,5-trimethoxy-amphetamine (TMA), which is also a metabolite of elemicine (a constituent of nutmeg), and 4-bromo-2,5-dimethoxyamphetamine (DOB), have been almost completely displaced by the methylenedioxyamphetamines and today play an insignificant role in the drug scene. 

Cactus alkaloids. About 2000 cactus species (stem succulents) of tropical and subtropical desert areas are known, some of which contain h lucinogenic principles, e. g., Lophophora species indigenous to Mexico together with other hallucinogenic cacti the latter are known as peyote (see Lophophora alkaloids). They contain ca. 5% alkaloids such as mescaline, anhalo-nine, lophophorine, pellotine, etc., mainly isoquinoline alkaloids, and phenylethylamine alkaloids. 

The simple alkaloid mescaline is the main active component of L. ml-liamsii of (10) and o Trichocereus pachanoi of (12), and the yield of mescaline is said to be 2% of the dried material. Mescaline is a phenethylamine (=phenylethylamine) type alkaloid, like ephedrine. 

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