Reserpine from Rauwolfia

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. 

A new weak base, neonor-reserpine, from Rauwolfia vomitoria, is regarded as a stereoisomer of psuedoreserpine 45 since the new base appears to have the epiallo stereochemistry, it must differ from pseudoreserpine in the stereochemistry at one or more of the positions C-16, C-17, and C-18. 

Another fruitful means of identifying pharmacologically active natural products has been that of folk law remedies, many of which are plant products. Typical examples include alkaloids, such as atropine (from plants of the Solanaceae family, known to the ancient Greeks) and reserpine (from Rauwolfia serpentina, the snakeroot), which is popular in India as a herbal remedy for use as a tranquilizer or antihypertensive. Other chapters in the book relate to stigmines (based on phy-sostigmine, an anticholinesterase alkaloid from the Calabar bean in West Africa) that are used to treat Alzheimer s disease (Chapter 11-12), and opioid receptor ligands (based on morphine, the most important alkaloid of the opium poppy) for pain relief and as antitussives (Chapter 11-11). 

In the history of ethnopharmacology, a most significant event was the isolation and clinical application of the alkaloid reserpine from Rauwolfia spp, a plant that had been used for millennia in the Ayurvedic tradition to treat "madness". Although reserpine had clearly demonstrated antipsychotic efficacy, it was soon replaced by the first synthetic antipsychotic, chlorpromazine, which proved more effective, had fewer side-effects and was relatively inexpensive to manufacture [44]. Exhibit 4 provides overviews for representative studies on natural products with putative anti-psychotic effects. 

In the families of the Apocyanaceae, Loganiaceae, Rubiaceae, and Euphorbiaceae, indole alkaloids of complicated structure are found which can be arranged in different groups. We may take reserpine from Rauwolfia serpentina as an example. A sinapic acid residue is present as part of the molecule, in addition to the basic skeleton of tryptophan and two 5 C units (Fig. 130). 

Some examples ofplant alkaloids. Coniine is from the leaves and seeds of hemlock and very toxic to motor nerves. Strychnine, from Strychnos nux-vomica, is a central nervous system and respiratory stimulant, also very toxic. Reserpine, from Rauwolfia serpentina roots, is used clinically against hypertension and formerly as a tranquillizer... 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Reserpine A drug extracted from Rauwolfia serpentina which was once clinically used in the treatment of essential hypertension and schizophrenia. 

The isolation of a new reserpine-type alkaloid from Rauwolfia vomitoria Afz. named neonorreserpine has recently been reported however, the stereochemistry of its substituents attached to ring E has not yet been established (86). 

The isolation of methyl reserpate (121) from Rauwolfia vomitoria Afz. (42) and R. obscura K. Schum. (88) and of methyl deserpidate (122) from Rauwolfia obscura K.Schum. (89) has been reported by Court and coworkers. It should be mentioned that these compounds may not be primary products but only artifacts formed by hydrolysis of reserpine (109) and deserpidine (110), respectively. 

Other plants known to contain psychoactive compounds include hellebore, which was used for centuries in Europe to treat mania, violent temper, mental retardation and epilepsy. However, a drug of major importance in modern psychopharmacology arose from the discovery by medicinal chemists of the alkaloids of Rauwolfia serpentina, a root which had been used in the Indian subcontinent for centuries, not only for the treatment of snake bite but also for alleviating "insanity". Understandably, the mechanism of action of reserpine, the alkaloid purified from Rauwolfia serpentina, helped to lay the basis to psychopharmacology by demonstrating how the depletion of central and peripheral stores of biogenic amines was correlated with a reduction in blood pressure and tranquillization. 

Reserpine is a neuroleptic and an antihypertensive medication obtained from Rauwolfia... 

No studies were found on the hypnotic activity of the phenolic acids however, the hypnotic activity of alkaloids is known. Dl-Tetrahydropalmatine (dl-THP), a naturally occurring alkaloid, has been intensively studied for its sedative and hypnotic effects. A putative explanation for its mechanism and target of action involves the dopaminergic neurotransmission system [371]. Reserpine, an alkaloid from Rauwolfia serpentina Benth. ex Kurz, was widely used for its antihypertensive action. Flowever, its use has been reduced because of its... 

For a few years, hexamethonium and hydralazine were mainstays in the treatment of severe hypertension. They were reasonably effective in lowering blood pressure, but often caused severe side-effects. The final dmg developed in those early days, reserpine, was the product of more than two decades of research into compounds derived from Rauwolfia serpentina, a plant used for centuries by physicians and herbalists on the Indian subcontinent. The quality of the result obtained with the various dmgs used in mono- or combined therapy to treat hypertension proved clearly that fatal outcomes associated with this disease are caused by high blood pressure. ... 

In 1952, reserpine had been isolated from Rauwolfia and eventually was used for treating essential hypertension. 

Among its first applications was the study of reserpine. Reserpine was isolated in 1952 from Rauwolfia serpentina (Indian snakeroot), which was used for centuries to treat insanity. Reserpine acts by blocking the reuptake NE back into presynaptic vesicles. The same year, Henri Laborit, a surgeon in Paris, administered reserpine to prepare his patients for surgery, because it maden them less anxious. Subsequently, it was widely used to treat patients with severe psychiatry diseases with impressive results. 

Among these preparations are a few, which have found their way into Western pharmacology. These include extracts from the camphor tree (Cinnamomum camphora), from hemp (Cannabis sativa), from various Rauwolfia species (e.g. reserpine), from ginseng (Panax quiti-quefolium and Panax schinseng) and from Ma-huang (Ephedra sinica). 

It is a common knowledge that plants are useful sources of many valuable medicines. Among these medicines several indole alkaloids can be found, e.g. reserpine and deserpidine from Rauwolfia serpentina ajmalicine and yohimbine from Corynanthe yohimhe vinblastine and vincristine from Catharanthus roseus just to mention a few of them. 

If the active principle or the group of active substances in the extract has been identified — such as reserpine in rauwolfiae extract or anthraquinones in senna extract — then the other substances contained are, at least from the point of view of the analyst, considered to be of secondary importance. These extracts have a permitted variabifity of the defined range of constituents and it should not exceed a numeric difference of +5% (more than +5% in rare cases). 

Ikram and Bakhsh [94] have separated five of the best known alkaloids from Rauwolfia serpentina on a loose alumina layer. Amongst older work, that of Waldi and co-workers [257], Teichert et al. [241] and ScHLEMMER and Link [203] are mentioned here. The last named authors have also worked out a method for quantitative determination of reserpine and other Rauwolfia alkaloids in this, the spot, detectable... 

Reserpine (Fig. 4), an alkaloid extracted from Rauwolfia serpentina, and many other natural or synthetic substances block the storage of monoamines (catecholamines as well as 5-HT) the resulting depletion of the amine stores is accompanied by a rise of acidic metabolites in the urine. This property of reserpine-like compounds to deplete monoamines stores has great experimental and clinical value... 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

In 1952 reserpine, an alkaloid extract from the Indian snakewort plant, Rauwolfia serpentina, which had been used in that country to treat madness , was first tried in schizophrenia. The beneficial impact on patients and the hospital wards was dramatic, as was that a year later of chlorpromazine, a phenothiazine derivative and haloperidol, a butyrophenone. These latter two drugs and closely related derivatives remained the mainstay of therapy for almost 40 years. 

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