Phenethylamine alkaloids Peyote

More than 55 alkaloids have been isolated from peyote. Mescaline (3,4,5-trimethoxy-j8-phenethylamine) is the primary psychoactive alkaloid of the peyote cactus, and by far the one that has been most studied (figure 9.6). These may be categorized into phenethylamines (including mescaline), isoquinolones, and Krebs acid conjugates. See table 9.2 for a partial list of peyote alkaloids. 

One part is the large collection of psychoactive compounds known as the phenethylamines. The first known plant psychedelic was mescaline, or 3,4,5-trimethoxyphenethylamine. This simple one-ring alkaloid was discovered in the North American dumpling cactus Peyote (Anhalonium williamsii) in the late nineteenth century, and is now known to be a component of over fifty other cacti. Over a dozen other cactus phenethylamines have been isolated and identified, and there are perhaps a hundred synthetic analogues that are now also known to be psychedelic in action. This body of information has been published by my wife Ann and me as a book entitled "PIHKAL A Chemical Love Story." PIHKAL stands for Phenethylamines I Have Known and Loved. 

Dopamine may alternatively be formed from tyrosine via hydroxylation of L-dopa which is decarboxylated. However, inverse isotope dilution experiments to study the formation of dopamine and dopa have shown that this is probably a minor pathway in peyote (176). It has been shown that L-tyrosine is incorporated into alkaloids in peyote three times more efficiently than into protein (344). 4-Hydroxy-3-methoxyphenethylamine can be methylated to 3,4-dimethoxy-phenethylamine (homoveratrylamine), which may be viewed as a dead-end product in Scheme 2 (10, 203). Phenylalanine is probably not a precursor of the... 

Isoquinoline Alkaloids.—This year has seen the solution of a longstanding mystery in alkaloid biosynthesis the origin of the extra skeletal carbons of the peyote cactus alkaloids, anhalonidine (43) and anhalamine (47). The major portion of the skeleton is derived in each case from tyrosine, by a well established29,30 pathway leading to the intermediate phenethylamine (41) but, despite much research, the origin of C(l) of (47) and C(l) + C(9) of (43) remained unsolved. 

The extra carbon [C(l)] of anhalamine (47) is derived in a similar way.33 In this case the corresponding carboxylic acid, peyoxylic acid (46), labelled with l4C at C(l), was incorporated specifically into the alkaloid. The amino-acid was also identified as a natural product of the peyote cactus. Presumably peyoxylic acid is derived in the plant by condensation of the phenethylamine (41) with glyoxylic acid (Scheme 6). 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

Peyote Alkaloids.—An O-methyltransferase has been isolated from the peyote cactus. Its ability to catalyse the methylation of various phenolic phenethylamines and isoquinolines, and the site of methylation, has indicated possible biosynthetic relationships within the peyote cactus cf. ref. 3. 

Quite simply, mescaline is a major component and a centrally active alkaloid of the Peyote plant. It is a phenethylamine, which can undergo a cyclization within the plant to produce a pile of derivatives (tetrahydroisoquinolines) such as anhalonine and 0-methylanhalonidine that are marvelously complex alkaloids, all natural components of this magical cactus. But there is another pile of derivatives (tetrahydroisoquinolines) such as anhalonine, and lophophorine, and peyophorine which are the logical cyclization products of another phenethylamine which does not exist in the cactus. 

The Mexican peyote cactus, Lophophora williamsii, is the cactus species appearing to be richest in alkaloids. This Httle spineless sage-green cactus has over the years enjoyed widespread interest, mainly because of its content of the hallucinogenic phenethylamine mescaline, fts natural habitat is northern Mexico and the southern parts of Texas, USA (Anonymous 1959). 

The simple isoquinolines, anhalonidine (12) and anhalamine (13) are bio nthesized in the peyote cactus along with the hallucinogenic phenethylamine, mescaline (6). It is clear, by inspection, that the isoquinoline alkaloids, (12) and (13), are formed from an Ar-C2-N unit like that seen in mescaline (6) with the inclusion of an additional or C2 unit. 

The pathways leading to these bases, which begin in primary metabolism with the a-amino-acid, tyrosine (1) are known in considerable detail. This is the result of quite extensive experiments particularly with various phenethylamine precursors (Lund-strom 1971, Herbert 1980). A key intermediate is 3,4-dihydroxy-5-methoxyphene-thylamine (5) which stands at a fork leading separately to mescaline (6) and the isoquinoline alkaloids methylation at C-3 leads to mescaline (6) whereas methylation at C4 ultimately affords anhalonidine (12) and anhalamine (13) (Fig. 1). The pathways which have been deduced leading to mescaline (6) and to (7) are nicely supported by a Study which explored the specificity of methylation by an O n ethyl transferase isolated from peyote (Basmadjian and Paul 1971, Basmadjian et al. 1978). 

Barton DHR, Cohen T (1957) In Festschrift Dr A Stoll, Birkhauser, Basel, p 117 Barton DHR, Kirby GW, Taylor JB, Thomas GM (1963) Phenol oxidation and biosynthesis, part VI. The biogenesis of amaryllidaceae alkaloids. J Chem Soc 4545—4558 Barton DHR, Hesse RH, Kirby GW (1965) Phenol oxidation and biosynthesis, part VIII. Investigations on the biosynthesis of berberine and protopine. J Chem Soc 6379-6389 Barton DHR, Bracho RD, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIV. Origin of chirality in the erythrinan system and derivation of the lactone rings of a- and ]3-erythroidine. J Chem Soc Perkin Trans 1 2278-2283 Basmadjian GP, Paul AG (1971) The isolation of an O-methyltransferase from peyote and its role in the biosynthesis of mescaline. Uoydia 34 91-93 Basmadjian GP, Hussain SF, Paul AG (1978) Biosynthetic relationships between phenethylamine and tetrahydroisoquinoline alkaloids in peyote. Lloydia 41 375-380 Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H (1964) Alkaloid biosynthesis, part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc 3600-3610... 

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