Pharmacology of rauwolfia alkaloids, including reserpine

Use of rauwolfia serpentina benth. in neuropsychiatric conditions

Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr.

An overview on synthetic entries to tetrahydro-β-carbolines

The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.

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A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine

Rauwolfia is an important genus of the plant family Apocynaceae. There are nearly one hundred and twenty‐five species of Rauwolfia which are distributed all over the tropical regions of the world (1‐8). The most important member of the genus is R. serpentina Benth; the crude drug was known to the ancient Indians as a useful febrifuge (8), a remedy for snake bite, and as a cure for dysentery. In more recent times it has been used for insomnia, hypochondria and insanity.

The presence of alkaloidal principles in R. serpentina was first pointed out in 1890 by Greshoff (9). In 1933, Chopra, Gupta, and Mukherjee (10) reported the hypotensive activity of the material extracted from the plant and in 1931 Siddiqui and Siddiqui (11) isolated a series of crystalline alkaloids from R. serpentina. Active chemical and pharmacological interest in R. serpentina has resulted in the discovery of several new alkaloids (Table I). The isolation by Muller, Schlittler, and Bein (12) of reserpine, an alkaloid with pronounced hypotensive and sedative activity, has lent further impetus to the pharmacological and chemical study of the alkaloids of R. serpentha. A brief summary of the chemical aspects of R. serpentina will be presented in this review.

The alkaloids of Rauwolfia serpentina benth

9,10-Dihydrophenanthrene



reactant: phenanthrene




product: 9,10-dihydrophenanthrene





Keywords:

reduction, CC  HCCH;
catalysts, metal, copper chromite;
phenanthrene;
catalysts, metal, Raney nickel W-6;
sodium;
sodium, disposal

Donald D. Phillips

Papers

The alkaloids of Rauwolfia serpentina benth

9,10‐Dihydrophenanthrene