Tryptophan reserpine

No direct evidence has been provided for the view that, notwithstanding a fall in the total brain 5-hydroxytryptamine content, the availability of the free amine is increased. In animals whose brain 5-hydroxytryptamine has been greatly reduced by dietary restriction of tryptophan, reserpine has its usual sedating action. The suggestion that the excitatory actions of 5-HTP are due to the inhibition, by large quantities of 5-hydroxytryptamine, of neurones which are stimulated by the smaller quantities liberated by reserpine is not supported by the observation that 5-HTP is incapable of reversing the action of reserpine. Finally, no consistent correlation has been found between the amount of 5-hydroxytryptamine in brain, or in any of its subcellular fractions, and the extent of behavioural depression. 

The indole ring system appears in many naturally-oeeuring substances including the amino acid tryptophan and the drug reserpine. 

There are a few substances that can reduce serotonin, norepinephrine and/or dopamine rapidly and substantially, reducing them to levels thought to be lower than those of depressed patients.23 That is what reserpine was supposed to do and, as we have seen, it did not cause depression - despite the early clinical impression that it did. Other substances have been used in later studies, the most common of which are amino-acid mixtures that lack the essential amino acids needed by the body to produce these neurotransmitters. For example, having people drink a beverage that is rich in amino acids, but does not contain tryptophan (the amino acid needed to produce serotonin), lowers their serotonin levels within a couple of hours. 

A second, more extensive experiment involved oral administration of three daily doses (100 mg/kg) of parachlorophenylalanine (PCPA). This tryptophan hydroxylase inhibitor (47), like reserpine, enhanced the behavioral effects of LSD (13) moreover, hypersensitivity occurred when 5-HT, but not other monoamine, concentrations were below normal in both forebrain and hindbrain (13). That is, effects were observed at 5 and 12 days (when 5-HT was depleted to 10-20% and 60-70% of normal) but not at 21 days (when 5-HT had returned to normal). Control experiments (13) indicated that (a) the interaction of PCPA, 5-HT, and LSD was probably not caused by generalized hyperactivity or hyperirritability sometimes seen after PCPA (73) (b) PCPA does not affect threshold doses of other psychoactive but nonserotonergic compounds, such as d-amphetamine (0.3 mg/kg) and (c) pretreatment with a-methylparatyrosine, a tyrosine hydroxylase inhibitor which depletes catecholamines rather than indoleamines, does not alter sensitivity to LSD. 

Hermoni M, Lerer B, Ebstein RP, et al Chronic lithium prevents reserpine-induced supersensitivity of adenylate cyclase. J Pharm Pharmacol 32 510-511, 1980 Hertzman PA, Blevins WL, Mayer J, et al Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan [see comments]. N Engl J Med 322 869-873, 1990... 

Synthesis inhibitors block tryptophan hydroxylase, the first rate-determining enzyme in serotonin synthesis. Although p-chlorophenylalanine (4.111) can decrease serotonin levels by more than 90%, this agent does not cause the sedation that is seen after catecholamine depletion with reserpine. Therefore, reserpine, although capable of depleting 5-HT vesicles, causes sedation by a catecholaminergic mechanism that inhibits uptake-2. It acts on the membrane of the synaptic vesicle and seems to prevent 5-HT and catecholamine uptake into the granule. 

Indoles are very important in medicinal chemistry. The indole moiety is electron-rich so it is very easily oxidized. One example of severe cleavage of the indole ring is the oxidation of tryptophan to V-formylkynurenine. An example of milder oxidation of indoles is reserpine degradation. Reserpine, an indole alkaloid, spontaneously decomposes in chloroform solution to give oxygenated products (58) (Fig. 11). Reserpine 7-hydroperoxide (XIV) was isolated in the reaction mixture this is the key intermediate in the oxidative pathways of many indoles (59). 

The biosynthetic pathways of reserpine and other alkaloids of Rauwalfia have been extensively studied by several authors. Leete (l8, 19) fed DL-[2- C]-tryptophan into Rauwolfia serpentina (3 years old plants) which led to the formation of radioactive ajmaline, serpentine and reserpine (18). Later, he found that radioactive serpentine was labeled solely at C-5 indicating that tryptophan was a direct precursor of the -carboline moiety of this alkaloid (19). Other radioactive precursors have been administered to Rauwolfia plants such as [l- C] acetate (20), [2- C] acetate (21), [2-11 C] alanine (20) and [2-l2 C] glycine (21, 22). All incorporated into ajmaline and reserpine. 

A specific cleavage reaction of NH2-terminal tyrosyl dipeptides occurred upon their treatment with DIB in methanolic potassium hydroxide. Tyrosine itself was converted into 4-hydroxybenzyl cyanide (52%) under these conditions [69], A related cleavage of tryptophan and several derivatives of it, including dipeptides, led to the formation of 3-methoxyindole [70]. Reserpine and also 2,3-dimethylindole reacted in the same way in the presence of alcohols, affording 3-alkoxyindolenines... 

Figure 1.10 Schematic model of a central serotonergic neurone indicating possible sites of drug action. Tryptophan is converted to 5-hydroxytryptophcm (5-HTP) by tryptophan hydroxylase (1) and this enzyme can be inhibited by parachlorophenylalanine (pCPA) but this compound has only experimental value. 5-HTP is then converted to 5-HT and stored in vesicles (2), a process disrupted by reserpine and tetrabenazine. 5-HT is released by a Ca -dependentprocess (3) parachloramfetamine andfenfluramine increase 5-HT release while activation of 5-HTib/d autoreceptors inhibits release (at the cell bodies this function is served by 5-HTia receptors). After release 5-HT activates a range of postsynaptic 5-HT receptors (4) to produce functional responses and...

Much more complex are the thousands of alkaloids that include an indole (or 2,3-dihydroindole) sub-unit and in each of these one can discern the tryptamine nnit of the biosynthetic precursor tryptophan strychnine (33.3.2) (Strychnos nux vomica), vincristine (33.7) (Catharanthus roseus), and the antipsychotic and antihypertensive reserpine (Rauwolfia serpentina) are examples. A group of amides of lysergic acid, for example, ergotamine, occur in ergot fnngi (e.g. Claviceps purpurea), the remainder of the molecule comprising proline, phenylalanine and alanine nnits. Lysergic acid diethylamide is the notorious LSD. 

It should be mentioned that / -chlorophenylalanine (fenclonine) is an irreversible inhibitor of tryptophan hydroxylase, the first and rate-determining step in serotonin synthesis. Even though the efficiency of this decrease in 5HT may be as high as 90%, sedation does not result. Reserpine alkaloids, which also deplete 5HT and NE, are sedative. That leaves catecholamine depletion as relevant to sedation. It is interesting that p-chloropheny-lalanine is used to treat carcinoid syndrome, which is a nonmalignanf intestinal mucosal tumor pouring prodigious amounts of 5HT into the circulation. 

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