Rauwolfia alkaloids reserpine

Most DA (up to 75%) is stored in vesicles like NA. This can be disrupted by the rauwolfia alkaloid, reserpine and by drugs like tetrabenazine. It should be emphasised that these drugs deplete the neurons of amines by stopping their incorporation into... 

Reserpine and Related Alkaloids. Rauwolfia alkaloid reserpine (109) and a... 

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

Reserpine. As mentioned earlier, the Rauwolfia alkaloid reserpine is noted for its ability to deplete aromatic biogenic amines in nervous tissue of mammals and insects. One of the more remarkable effects of reserpine in humans is to render individuals indifferent to environmental stimuli. Reserpine appears to have a similar effect on insects, although information is still relatively scanty. In the cockroach, Periplaneta americana, reserpine at 50 vg/g causes strong and long-lasting depletion of the aromatic biogenic amines dopamine, octopamine, and 5-hydroxytryptamine (24). Numerous authors have noted that reserpine has tranquilizing effects on insects, e.g., the ant Formica rufa (30) and . americana (24,31). 

Furthermore, the rauwolfia alkaloids (reserpine and others), which also began to be used at that time in psychiatry (and as antihypertensives see Chapter 10), were found to be potent depletors of brain NE and 5-HT in animals. These and additional findings over the next decade led to the (mono)amine hypothesis of mental disorders. The DA hypothesis of schizophrenia is currently the one with the most supportive evidence. 

The primary limiting effect of reserpine is depression. Depletion of central monoamines is believed to be the mechanism for this effect (Heninger et al. 1996 Charney 1998). The depression may occur in a gradual and insidious manner, and the causal association between the drug and depression may be missed (Oates 1996). Rauwolfia alkaloids are contraindicated in anyone with a history of depression, and careful vigilance is required to ensure that they do not induce depression in otherwise normal individuals. Additional side effects are sedation and difficulty with concentration and performing complex mental tasks. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Reports have recently been published of protonation at C-7 (a prerequisite for Mechanism 1) under strongly acidic conditions [16,17]. While investigating the protonation site of Rauwolfia alkaloids, Balon and co-workers [16] showed through l3C NMR studies that protonation takes place at C-7 in 18M H2S04. Experiments by Royer et al. [17] indicated that reserpine (1) and isoreserpine (2) are transformed into the corresponding 2,7-dihydro compounds (14) (55%) and (15) (87%) by NaBH3CN in TFA at room temperature, Scheme (6). This is only possible through protonation at C-7. Further evidence was provided by deuterium incorporation at C-7 when TFA-d was used. 

The rauwolfia alkaloids are now hardly ever prescribed in the UK, either as antihypertensives or as tranquillizers. Over a period of a few years, they have been rapidly superseded by synthetic alternatives. Reserpine has also been suggested to play a role in the promotion of breast cancers. Both ajmalicine (= raubasine) (Figure 6.76) and ajmaline (Figure 6.82) are used clinically in Europe, though not in the UK. Ajmalicine is employed as an antihypertensive, whilst ajmaline is of value in the treatment of cardiac arrhythmias. Ajmalicine is also extracted commercially from Catharanthus roseus (see page 357). 

Within the last 10 years, Rauwolfia products have become important therapeutic agents, both as sedatives and antihypertensives. Although their production and use have fallen off since the peak years of 1955 and 1956, it is estimated that their total sales at the consumers level in 1961 still amounted to 100 million in the United States alone. Since 1952, the year reserpine was first isolated, several thousand articles have been published on the isolation, chemistry, pharmacology, and clinical aspects of reserpine and other Rauwolfia alkaloids, and today these investigations are still being pursued. Botanists estimate the number of identified Rauwolfia species to be about 50, of which R. serpentina,... 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

The Rauwolfia alkaloids, including reserpine, are now little used. They act by depleting neurotransmitter stores of catecholamines and reducing sympathetic nervous activity, but their effects are non-specific, and nervous system adverse effects (depression, drowsiness, tiredness, confusion) are prominent. There is also a troublesome incidence of diarrhea, hjrperprolactinemia, gynecomastia, and a possible withdrawal syndrome. 

Early retrospective studies suggested that reserpine was associated with breast cancer, but prospective studies and meta-analyses of case-control studies have shown only a weak association (6). In vitro studies have shown that rauwolfia alkaloids are not genotoxic or mutagenic... 

Reserpine is a Rauwolfia alkaloid that has been used for centuries to treat insanity, insomnia and hypertension in humans. Reserpine inhibits normal sympathetic activity in both the CNS and the peripheral nervous system by binding to catecholamine storage vesicles, causing catecholamines to leak into the synapse so that they are not available for release when the presynaptic neuron is stimulated. This prevents the normal magnesium and ATP-dependent storage of catecholamines and 5-hydroxytryptamine in nerve cells, the result being catecholamine (norepinephrine (noradrenaline)) depletion. This results in the inhibition of normal sympathetic activity. 

Rauwolfia alkaloids, especially reserpine, which inhibit the monoamine transporters, were at one time used to treat hypertension, but the side-effects are marked. 

In practice, the method is considerably more diflBcult than the simplicity of the design suggests. The series of studies conducted on the possible relationship of the Rauwolfia derivatives to various cancers is testimony to the conflicting findings that may result. Indeed, the 11 case-control studies on reserpine and other Rauwolfia alkaloids reviewed by... 

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