Tryptamine derivatives, structure

Regioselective nucleophilic substitution at the 5 position is proved to occur when 1-hydroxytryptophan and -tryptamine derivatives are treated with 85% HCOOH (99H1157). Truly amazing is the fact that only substrates carrying a C—C—N structure in the side chain at the 3 position can undergo this regioselective substitution. 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

TABLE 3. Structures of tryptamine derivatives which have been studied tor potential hallucinogenic activity... 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

Non-tryptamines.—The structure (1) of a new bromo-indole derivative, isolated from an Australian sponge of the genus Iotrocha, has been elucidated and confirmed by synthesis.4 The indole-3-acetic ester of myo-inositol occurs in rice kernels (Oryza sativa) 5a this is the first reported occurrence of this ester in a plant other than maize (Zea mays). 

When the structural types in figure 3 are compared, it is striking to see how often indole structures appear, and always in the form of tryptamine derivatives. These may be tryptamines without any substitution in the indole nucleus or with hydroxy- methoxy- or phosphoryloxy-groups in the phenol ring of the indole or else the... 

Since they are tryptamine derivatives, the indolic hallucinogens are structurally related to the neurohumoral factor serotonin (5-hydroxytryptamine). Serotonin is widely distributed in warmblooded animals. It accumulates in the brain, where it plays a role in the biochemistry of nervous regulations. Consequently, it seems that certain tryptamine structures which occur so frequently in hallucinogens, as well as in the neurohormone serotonin, may be biochemically important in the metabolism of psychic functions. . . ... 

The discovery that tryptamine is also an endogenous enhancer substance (Knoll 1994) opened the way for a structure-activity relationship study aiming to synthesize a new family of enhancer compounds structurally unrelated to PEA and the amphetamines. J -(-)-l-(benzofuran-2-yl)-2-propylaminopen-tane [ (-)-BPAP ] was selected as a tryptamine-derived synthetic mesencephalic... 

Figure 3.10 shows the chemical structure and pharmacological spectrum of tryptamine and two of the tryptamine-derived synthetic mesencephalic enhancer substances. 

Studies on known alkaloids include one on the AA BB system and the conformational populations of tryptamine and some N-substituted derivatives, and X-ray crystal structure analyses of psilocybin " and psilocin. " In connection with the separation and identification of tryptamine derivatives in the cerebrospinal fluid of schizophrenic patients the g.l.c. analysis of the heptafluorobutyroyl derivatives is recommended success is claimed on picogram quantities of material. ... 

Since tryptophan is recognized as a main constituent of plant proteins and as a common biogenetic precursor of the complex indole alkaloids, the wide occurrence of tryptamine derivatives in the plant kingdom is not unexpected. The presently known cases of these simple indole alkaloids have been ones in which a tryptamine unit formally appears as a slightly modified structure (e.g., by oxidation or methylation), as a cyclized form or a dimeric variation thereof, or as a modification which incorporates short carbon chains (e.g., C4, C2) or a simple aromatic structure (anthranilic acid) respectively. The great majority of the simple indole alkaloids are confined to the dicotyledon plants. 

Table I is a compilation of plant species which contain the simple indole alkaloid types of Fig. 1. As mentioned earlier, the main requirement for the inclusion of a certain simple indole alkaloid into Table I is that it contain a tryptamine unit as a readily distinguishable feature in its structure. That tryptamine is a precursor in the biosynthesis of many of the b, c, d, and e type simple indole bases is yet to be shown although it is felt that future work will prove the correctness of such a view. Gramine, the simplest indole alkaloid, has been included in the tryptamine classification a because it is biosynthetically related to tryptophan cryptole-pine has been likewise included therein although its structural relationship to tryptophan appears more obscure (Volume VIII, Chapter 1, pp. 4, 19). The calycanthine type does not possess a tryptamine structure but it is included in the simple indole alkaloid b classification since most of its congeners are tryptamine derivatives and since it exhibits a close biogenetic relationship to this latter (chimonanthine) type (Volume VIII, Chapter 16). Type d is represented by the small number of the so-called canthin-6-one alkaloids (Volume VIII, pp. 260-252, 497-498). The most recent variation of the simple indole alkaloids is found in the Anacardiaceae family. Its indoloquinolizidine nucleus suggests inclusion with type d on the basis of structural and biogenetic similarity. Finally, simple indole alkaloid type e is composed of the well-defined evodiamine (rutaecarpine) structural form (Volume VIII, Chapter 4).

Sec Table III for structures of some p choactive synthetic tryptamine derivatives. ... 

The activity of some tryptamine derivatives as MAOIs has been investigated (Ho et al. 1970 Lessin, Long 8c Parkes 1967 Barlow 1961). Unlike the carbo-lines, however, extensive studies of the structure-activity relationships of tryptamines with respect to MAOI activity have not been carried out. Lessin, Long Parkes (1967) examined the structure-activity relationships of a series of substituted tryptamines and 0-carbolines on... 

Although the available literature indicates that MAOIs do have agnificant influences on both the metabolism and behavioral effects of DMT, apparently the specific interactions of DMT with 3-carbolines have not been investigated. This apparent oversight is especially remarkable in view of the close structural relationships of tryptamine derivatives and arbolines (see Tables 1 and II), the probable metabolic interconversion of DMT, other tryptamines and /J-carbolines (Barker, Monti 8c Christian 1980 Hsu 8c Mandell 1975), the involvement of both classes of compounds in important neuroregulatory functions such as MAO activity and... 

More recently, Kalaus and Szantay have made use of a similar approach to synthesize a variety of pentacyclic indole alkaloids containing the aspidospermane, ibophyUidine, and iboxyphylline core structures. In one approach, featured in the formal total synthesis of ( )-12-demethoxy-N(l)-acetylcylindrocarine (188) [73], a benzyl-protected tryptamine derivative 183 was treated with an appropriately substituted aldehyde (184) to form the enamine species 185a-b, which then underwent... 

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