Phenethylamine, 3,4,5-Trimethoxy

The 2-phenylcyclobutylamines Structures 14 and 15 have also been prepared (161). In contrast to the cyclopropylamine, however, 15 showed no clinical activity following oral administration of a dose up to 25 mg of the racemic hydrochloride (199). The trimethoxy congener 14 has not been tested. The appropriately ring-substituted tran.s-2-phenylcyclopentyl or cyclohexylamines have not been reported. Based on the apparent lack of activity for 15, as well as the lack of activity for alpha-ethyl phenethylamine derivatives, however, these might be predicted to be inactive. 

Phenylalanine derivatives, substituted either with 3,4,5-trimethoxy or 2,5-dimethoxy-4-methyl substituents did not show activity (46). Although these would yield potentially active phenethylamines if decarboxylated in vivo, neither is likely to be a substrate for decarboxylases in the CNS (62). Several additional side chain alkylated compounds are discussed in the next section as rigid analogs. 

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. 

EXTENSIONS AND COMMENTARY Some fifty years ago this material was given the name reciprocal mescaline in that it was believed to exacerbate the clinical symptoms in schizophrenic patients. In the original report, one finds Thus we have di scovered an extremely remarkable dependency of the intoxicating action upon the position of the three methoxy groups. Mescaline, the 3,4,5-trimethoxy-B-phenethylamine, produces in the normal subject a much stronger over-all intoxication than in the schizophrenic patient, whereas 2,3,4-trimethoxy-B-phenethylamine has quite the opposite effect. It has little action in healthy individuals, being almost without intoxicating properties, but it is very potent in the schizophrenic. The metabolic conversion products of the reciprocal mescaline will be further studied as soon as the study of the metabolism of the proper mescaline is complete. ... 

Mescaline is chemically classified as a phenethy-lamine. Some of its identified chemical compounds are 3,4,5-trimethoxy-beta-phenethylamine, 3,4,5-trimeth-oxybenzeneethanamine, 3,4,5-trimethoxyphene-thyla-mine, and mescaline. This chemical classification makes the drug different from the other hallucinogens, specifically the more popular LSD, which is classified as an indole. Its chemical formula is CnH17N03. 

The enzymic oxidative deamination of simple phenethylamines is exemplified by the reported bio transformations of mescaline (146) (114, 115) and ephedrine (148) (116). Mescaline is metabolized to 3,4,5-trimethoxy-phenylacetic acid by tissue homogenates of mouse brain, liver, kidney, and heart (114,115). 3,4,5-Trimethoxybenzoic acid is also formed as a minor metabolite. The formation of jV-acetylmescaline (147), a significant metabolite in vivo, was not observed in the in vitro studies. Both D-(—)-and L-(+)-ephedrine have been incubated with enzyme preparations from rabbit liver norephedrine (149), benzoic acid, and 1-phenyl-1,2-propanediol were characterized as metabolites (116). The D-(—)-isomer was the better substrate, being more rapidly converted. Similar results were previously reported with rabbit liver slices as the source of enzyme (153,154). The enzymic degradation of the side chain of /i-phenethylamines has been extensively investigated with nonalkaloid substrates such as amphetamine (151) and jV-methylamphetamine (150) (10,155-157), and the reader is referred to these studies for a more comprehensive coverage of this aspect of the subject. 

And, as a final note, be careful. The code TMT has two meanings. In the phenethylamine area it identifies the mescaline analogue, 3,4,5-trimethoxy-tranylcypromine (ortrans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine). This is entry 56, page 607 of PIHKAL, and check there for further details. Here, entries of trimethylated tryptamines will be preceded by the specific locations of the methyl groups prefixes with numbers, Greek letters, and/or N for nitrogen. 

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)... 

SYNS MEZCALINE MEZCLINE 3,4,5-TRIMETHO-XYBENZENEETHANAMINE 3,4,5-TRIMETHOXY-PHENETHYLAMINE... 

Slotta and Heller (109, 110) prepared their starting material, viz., trimethoxyphenylpropionic acid by condensation of the substituted benzaldehyde with malonic acid and reduction of the resulting cinnamic acid. Mescaline was then obtained by Hofmann degradation of the trimethoxyphenlypropionamide. Kindler and Peschke (103) synthesized very pure, crystallized mescaline by condensation of 3 4 5-trimethoxy-benzaldehyde with potassium cyanide, acetylation, and catalytic reduction to the amine. Slotta and Szyska (111, 112) improved Spath s first synthesis, obtaining mescaline directly by the electrolytic reduction of w-nitrotrimethoxystyrene. Hahn and Wassmuth (113, 114) started from elemicine and first prepared trimethoxyphenylacetaldehyde by ozonization. The oxime was then reduced to mescaline. Kindler (115) and Kindler and Peschke (38, 103) improved the catalytic reduction of w-nitrostyrenes to the corresponding phenethylamines. Hahn and Rumpf (116) described the preparation of mescaline by reduction of w-nitrotrimethoxystyrene with Adam s catalyst. A review has been published by Jensch (117). 

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