Phenethylamine alkaloids Cacti

Homemann, K.M.K. etai 1973. Cactus alkaloidsxii. p-Phenethylamine alkaloids of the genus Coryphantha Journal of Pharmaceutical Sciences 61 41—45. 

This cactus is an important source of the so-called phenylethylamine (phenethylamine) alkaloids with a C6C2N skeleton.The main component... 

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. 

Alkaloid isolations and structural elucidations are summarized in Table 1. The cactus Ariocarpus scapharostrus, which has not previously been investigated, afforded four phenethylamines including hordenine and iVJV-dimethyl-3,4-dimethoxyphenethylamine. This is the first recorded occurrence of the latter in a... 

Possibly as a result of the social implications of the hallucinogenic j5-phenethyl-amines and simple isoquinoline alkaloids, a large number of new plant species suspected to contain these structural types have been closely scrutinized with the aid of sensitive analytical methods. Thus, extensive screening of a large variety of cactus species has been carried out. G.c. analysis has indicated the presence of trace amounts of dimers and trimers of phenethylamine and tetrahydroiso-quinoline types " while combination g.c.-mass spectrometry has enabled rapid identification of alkaloids of 120 cactus species." High voltage electrophoresis has been used for quantitative alkaloid determination.Useful structural information may be obtained from the technique of chemical ionization mass spectrometry. ... 

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). 

E. intermedia collected in one area and in E. gerardiana. Specimens of E. intermedia collected in other areas contained N-methylephedrine in addition, as did E. gerardiana var. sikkimensis, E. nebrodensis var. procera, an unidentified Ephedra sp., and various commercial samples of the drug Ma-Huang. The cactus Opuntia clavata has been shown to contain iV-methyltyramine. Whereas no alkaloids could be detected in a number of Thelocactus spp., seven cacti of the genus Gymnocactus were found to contain various amounts of N-methyl- -phenethylamine, in some cases accompanied by hordenine and iV-methyltyramine. ... 

Norquist, D.G. and J.L. McLaughlin 1970. Cactus alkaloids viii. Isolation of A me-thyl-3,4-dimethoxy-p-phenethylamine from Ariocarpusfissuratus y-n.fissuratus Journal ofPharmaceuticalSciences 59 1840. 

Doetsch, EW. etal. 1980. Cactus alkaloids. XL. Identification of mescaline and other (3-phenethylamines inPereskia, Pereskiop-i/r, and Islaya by use of fiuorescamine con-JourmdofOrrormOographyr -. 79. 

Hidden in the old literature was the solution to the long-standing problem of the biosynthesis of the Cj unit (C-1 and C-9) of anhalonidine (12) and the C, unit (C-1) of anhalamine (13). Only recently was the original suggestion for the biosynthesis of these cactus alkaloids examined, with positive results. Thus the two acids (10) and (11) were found to be precursors for (12) and (13) respectively. They apparently derive in turn from the phenethylamine (9) and pyruvic acid or... 

The presently known cactus alkaloids are of simple chemical constitution. They are either substituted /3-phenethylamines, evidently related to and probably derived from the naturally occurring aromatic amino acids (tyrosine, dihydroxyphenylalanine, A -methyltyrosine, etc.), or they are simple tetrahydroisoquinolines that could originate from these bases by condensation and cyclization through the action of organic compounds containing one or two carbon atoms (formaldehyde and acetaldehyde equivalents ). 

Obviously, under these conditions, it will be quite possible to find bases of the same type in plants of widely separated botanical families or even in products of animal metabolism. The individual cactus alkaloids will be found, therefore, under the headings /8-Phenethylamines (see Vol. Ill, chap. 22) and Simple Isoquinoline Alkaloids (see Vol. IV, chap. 26), where are also included all other natural bases of similar structure but different origin. 

There is little doubt that other 8-phenethylamines will be found to be primary plant constituents and their structures can even be predicted based on the regularity with which the substituents appear to occur in the already known natural compounds. A missing link has been recently discovered by Kirkwood and Marion (4) in certain strains of barley. The newly found JV-methyltyramine completes the series which begins with tyramine and terminates in the quaternaiy cactus alkaloid candicine. 

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 Chenopodiaceae family is closely related to the Cactaceae, both belonging to the order of Caryophyllales. Four species of this family are known to contain simple tetrahydroisoquinoline alkaloids of the same kind as found in cactus species (Table 3). Salsola arbuscula was the first known natural source of salsoline and salsoUdine (Orekhov and Proskumina 1934). No phenethylamine derivatives are reported from the Chenopodiaceae species containing tetrahydroisoquinolines. However, another species of this family, Haloxylon salicornum (Moq.-Tand.) Boiss. is rich in substituted phenethylamines (Michel and Sandberg 1968) which further points at the close relationship with the Cactaceae family. 

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. 

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