Historical View on Ergot Alkaloids

A short survey of the history of ergot, of the original and, for a long time, only source of ergot alkaloids, is given. Once a dreaded poison, ergot has changed its role over the centuries to become a rich treasure house of valuable pharmaceuticals. In the Middle Ages it was the cause of epidemics of ergotism, which cost tens of thousands of people their lives. Ergot was first mentioned by the German physician Lonitzer in 1582 as a remedy used by midwives for quickening childbirth. The isolation of pharmacologically useful alkaloids started in 1906 with the discovery of ergotoxine and its adrenolytic activity by Barger, Carr and Dale. In 1918, Stoll isolated ergotamine, the first chemically pure ergot alkaloid, which found widespread therapeutic use in obstetrics and internal medicine. In 1935 the specific oxytocic principle of ergot, ergonovine, was discovered simultaneously in four separate laboratories. Since then, worldwide investigations on ergot alkaloids resulted in the elucidation of their structures and total syntheses and preparation of valuable therapeutics such as Methergine, Hydergine, Dihydergot, and others. The original and, for a long time, only source of ergot alkaloids was the sclerotium of the fungus Claviceps purpurea (Fries) Tulasne, which grows on rye and which is commonly known as ergot (Secale cornutum) (fig. 1). Ergot has a fascinating history. Over the centuries its role and significance have undergone a complete metamorphosis. Once a dreaded poisonous contaminant, it has changed to become a rich treasure house of valuable pharmaceuticals. Ergot began its history as a poisonous contaminant of edible grain. As early as 600 Be, an Assyrian tablet alluded to a 'noxious pustule in the ear of grain'. In the Middle Ages, bizarre epidemics occurred in Europe which cost tens of thousands of people their lives, caused by bread made from rye contaminated with ergot. These epidemics of ergotism occurred in two forms, as Ergotismus convulsivus which was characterized by nervous, convulsive symptoms, and as Ergotismus gangraenosus in which gangrenous manifestations leading to mummification of the extremities were a prominent feature. Ergotismus was also known as 'ignis sacer', 'holy fire' or 'St. Anthony's fire', because St. Anthony was the patron saint of a religious order, which was founded for the purpose of caring for the victims of ergotism. Figure 2 shows St. Anthony surrounded by patients stricken with ergotism. The cause of these epidemics, i.e., bread contaminated with ergot, was recognized as late as in the 17th century, and since then there have been only sporadic outbreaks of ergot poisoning. Ergot was first mentioned by the German physician Adam Lonitzer in 1582 as a remedy used by midwives for quickening childbirth. Fig. 2. St. Anthony surround'ed by patients stricken with ergotism. (Staatliche graphische Sammlung, Miinchen.) The first scientific report on the use of ergot as an oxytocic agent, 'Account of the pulvis parturiens', was given by the American physician John Stearns in 1808. But already in 1824, D.Hosack, recognizing the danger of using ergot for accelerating childbirth, recommended that the drug be used only to control postpartum hemmorrhage. Since that time ergot has been used in obstetrics mainly for this purpose. The last and most important chapter in the history of ergot, and one which is stilf not completed, concerns ergot as a rich source of pharmacologically useful alkaloids. The Most Important Steps of Chemical Investigations of Ergot Alkaloids (1, 2) It started with the isolation of ergotoxine in 1906 by Barger and Carr and the discovery of its adrenolytic activity by Dale. In 1918, Stoll isolated ergotamine, the first chemically pure ergot alkaloid which found widespread therapeutic use in obstetrics and internal medicine. The next important step was the discovery in 1935 of the specific oxytocic principle of ergot by Dudley and Moir, which resulted in the isolation of the alkaloid ergonovine (also named ergometrine, ergobasine, ergo to cine ) simultaneously in four separate laboratories. Since 1935, extensive investigations on the chemistry of ergot alkaloids have been carried out, mainly by Jacobs and Craig in the United States, Smith and Timmis in England, Stoll, Hofmann et al. in Switzerland, paralleled by pharmacological and clinical investigations by Rothlin, Cerletti et al. The most important steps in these investigations were the following: identification of the common nucleus of all pharmacologically important ergot alkaloids by Jacobs and Craig, which they named lysergic acid, in 1934; discovery of iso1ysergic acid by OH I C-OH Smith and Timmis in 1936, isolysergic acid being the nucleus of the pharmacologically inactive isomers of ergot alkaloids; elucidation of the structure of lysergic and isolysergic acid by Jacobs and Craig and by Stoll, Hofmann and Troxler, which led to the final formula as depicted in figure 3, published in 1949. This constitution of lysergic acid and isolysergic acid was confirmed by total synthesis by Kornfeld et al. in the Lilly Laboratories in 1954. A different synthesis of lysergic acid was published by Julia et al. in 1969. Both syntheses are only of scientific interest; they cannot compete with the production of lysergic acid from natural sources. Lysergic acid, possessing two asymmetric centers, can exist in four stereoisomeric forms: d-Iysergic acid, d-iso1ysergic acid, I-lysergic acid and l-isolysergic acid. With very few exceptions, only the alkaloids or synthetic derivatives containing d-1ysergic acid show the high characteristic pharmacological activity. The first partial synthesis of a natural ergot alkaloid, namely of ergonovine, could be realized by Stoll and Hofmann in 1937, by connection of lysergic acid in the form of its reactive azide with L-2-amino-propanol (fig. 4). CH3 I CONHCH-CH20H ~ ' CO-T~~~-jj~~'~\?H