Tryptamines structure

Some neuroleptic agents, like cycloindole (497), which has a modified tryptamine structure, and flucindole (498), a difluoro analog of cycloindole, have found use in therapy because of their anti-depressant and anti-psychotic activity (463,464) (Scheme 4.11). 3-Chlorocarbazole (385) (see Scheme 2.102), isolated from female bovine urine, has Diazepam-like activity (354). 

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. . . ... 

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).

Novel 5-HT2A ligands were obtained by incorporation of the tryptamine structure into a bridged y-carboline. The most potent compounds of the series are substituted on the basic nitrogen atom with a butyrophenone chain [24]. The 7S,10R enantiomer displays the highest affinity for the S-HTja receptor. The 7R,10S enantiomer is slightly less active but more selective with respect to dopamine-D2 receptors [25] (Table 10). 

Figure 18.37 Representative examples of neuroactive N,N-dialkylated tryptamines. Structural key features also include the presence of H, OH or CH3O at the 4 and 5 position of the benzene ring.

Emphasis in recent applications of the method has been placed on the synthesis of tetra- and penta-cyclic structures containing a di-hydro-j8-carboline system or its equivalent. Thus the tetracyclic system 100 was obtained from the amide (99) of tryptamine and hip-puric acid. ... 

The interesting work of Hahn and Hansel, who prepared a tetracyclic lactam by intramolecular cyclization of the condensation product of tryptamine and a-ketoglutaric acid, is referred to in Section IV, B, 2. Condensation of tryptamine with a,a -diketopimelic acid (403) led, presumably by way of the 1-substituted tetrahydro-)S-carboline (404), which could not be isolated, to a product to which the tetracyclic structure 405 was assigned. 

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. 

Trace amines are a family of endogenous monoamine compounds including (3-phenylethylamine (PEA), p-tyramine (TYR), tryptamine (TRP) and octopamine (OCT). The trace amines share close structural similarity with the well known classical monoamine neurotransmitters such as dopamine (DA), norepinephrine (NE) and serotonin (5-HT). As their name suggests, trace amines occur in comparably much lower abundance than monoamine neurotransmitters. For historical reasons, other endogenous amine compounds which might share some structural similarities with PEA, TYR, TRP or OCT are not referred to as trace amines. 

Tryptamine itself is found in all major centers of the brain. Its physiologic role in central nervous system (CNS) function, however, remains unclear. 5-Hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the CNS. The structural similarity of the tryptamine-related hallucinogens with 5-HT presumably forms the neurochemical basis for their action within the CNS. 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

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 4 illustrates the use of the CAR technique to develop CL kinetic-based determinations for various analytes in different fields. As can be seen, the dynamic range, limit of detection, precision, and throughput (—80-100 samples/ h) are all quite good. All determinations are based on the use of the TCPO/ hydrogen peroxide system by exception, that for p-carboline alkaloids uses TCPO and DNPO. A comparison of the analytical figures of merit for these alkaloids reveals that DNPO results in better sensitivity and lower detection limits. However, it also leads to poorer precision as a result of its extremely fast reactions with the analytes. Finally, psychotropic indole derivatives with a chemical structure derived from tryptamines have also been determined, at very low concentrations, by CAR-CLS albeit following derivatization with dansyl chloride. 

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

For the purposes of this chapter, hallucinogens are divided into two separate categories. The first section covers the substituted phenylalkylamines, with the prototype for these structures being mescaline. The second category includes indole-based compounds, including various substituted tryptamines, beta-car-bolines, and LSD. 

Compounds such as LSD or the beta-carbolines do not possess a primary amino group, are not rapidly metabolized in comparison to, for example, tryptamine, and enter the brain readily certain substituent groups can alter this situation. Members of the phenylalkylamine and indolealkylamine families of hallucinogens can produce similar effects in animals but may be capable of producing distinctive effects in man. As yet, there is no satisfactory and comprehensive structure-activity relationship that encompasses both major classes of compounds. This may be due in part to unique metabolic and distributional characteristics associated with the individual ring systems. 

Gessner, P. K., Godse, D. D., Krull, A. H., and McMullan, J. M. (1968) Structure-activity relationships among 5-methoxy-N,N-dimethyltryptamine, 4-hydroxy-N,N-dimethyltryptamine (psilocin) and other substituted tryptamines. Life Sci., 7 267-277. 

Indole alkaloids from Tabernaemontana plants are all biogenetically derived from tryptophan (tryptamine) and secologanine, which constitute the indole and terpenic portions, respectively, and can be classified into nine main types depending on the structural characteristics of their skeleton (Fig. 1). 

The biogenic amines are the preferred substrates of MAO. The enzyme comes in two flavors, MAO-A and MAO-B, both of which, like FMO, rely on the redox properties of FAD for their oxidative machinery. The two isoforms share a sequence homology of approximately 70% (81) and are found in the outer mitochondrial membrane, but they differ in substrate selectivity and tissue distribution. In mammalian tissues MAO-A is located primarily in the placenta, gut, and liver, while MAO-B is predominant in the brain, liver, and platelets. MAO-A is selective for serotonin and norepinephrine and is selectively inhibited by the mechanism-based inhibitor clorgyline (82). MAO-B is selective for /1-phcncthylaminc and tryptamine, and it is selectively inhibited by the mechanism-based inhibitors, deprenyl and pargyline (82) (Fig. 4.32). Recently, both MAO-A (83) and MAO-B (84) were structurally characterized by x-ray crystallography. 

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