Historical View on Ergot Alkaloids

Abstract. A short survey of the history of ergot, of the original and, for a long time, only sourceof ergot alkaloids, is given. Once a dreaded poison, ergot has changed its role over the centuries tobecome a rich treasure house of valuable pharmaceuticals. In the Middle Ages it was the cause ofepidemics of ergotism, which cost tens of thousands of people their lives. Ergot was firstmentioned by the German physician Lonitzer in 1582 as a remedy used by midwives forquickening childbirth. The isolation of pharmacologically useful alkaloids started in 1906 with thediscovery of ergotoxine and its adrenolytic activity by Barger, Carr and Dale. In 1918, Stollisolated ergotamine, the first chemically pure ergot alkaloid, which found widespread therapeuticuse in obstetrics and internal medicine. In 1935 the specific oxytocic principle of ergot,ergonovine, was discovered simultaneously in four separate laboratories. Since then, worldwideinvestigations on ergot alkaloids resulted in the elucidation of their structures and total synthesesand preparation of valuable therapeutics such as Methergine, Hydergine, Dihydergot, and others.

The original and, for a long time, onlysource of ergot alkaloids was the sclerotium ofthe fungus Claviceps purpurea (Fries) Tulasne,which grows on rye and which is commonlyknown as ergot (Secale cornutum) (fig. 1).

Ergot has a fascinating history. Over thecenturies its role and significance have under-gone a complete metamorphosis. Once adreaded poisonous contaminant, it has changedto become a rich treasure house of valuablepharmaceuticals.

Ergot began its history as a poisonous con-taminant of edible grain. As early as 600 Be, anAssyrian tablet alluded to a 'noxious pustule inthe ear of grain'. In the Middle Ages, bizarreepidemics occurred in Europe which cost tensof thousands of people their lives, caused bybread made from rye contaminated with ergot.These epidemics of ergotism occurred in twoforms, as Ergotismus convulsivus which wascharacterized by nervous, convulsive symptoms,and as Ergotismus gangraenosus in which gan-grenous manifestations leading to mum-mification of the extremities were a prominent

feature. Ergotismus was also known as 'ignissacer', 'holy fire' or 'St. Anthony's fire',because St. Anthony was the patron saint of areligious order, which was founded for thepurpose of caring for the victims of ergotism.Figure 2 shows St. Anthony surrounded bypatients stricken with ergotism. The cause ofthese epidemics, i.e., bread contaminated withergot, was recognized as late as in the 17thcentury, and since then there have been onlysporadic outbreaks of ergot poisoning.

Ergot was first mentioned by the Germanphysician Adam Lonitzer in 1582 as a remedyused by midwives for quickening childbirth.

Fig. 2. St. Anthony surround'ed by patientsstricken with ergotism. (Staatliche graphische Samm-lung, Miinchen.)

The first scientific report on the use of ergot asan oxytocic agent, 'Account of the pulvisparturiens', was given by the American phy-sician John Stearns in 1808. But already in1824, D.Hosack, recognizing the danger ofusing ergot for accelerating childbirth, recom-mended that the drug be used only to controlpostpartum hemmorrhage. Since that timeergot has been used in obstetrics mainly for thispurpose.

The last and most important chapter in thehistory of ergot, and one which is stilf notcompleted, concerns ergot as a rich source ofpharmacologically useful alkaloids.

The Most Important Steps of ChemicalInvestigations of Ergot Alkaloids (1, 2)

It started with the isolation of ergotoxine in1906 by Barger and Carr and the discovery ofits adrenolytic activity by Dale. In 1918, Stollisolated ergotamine, the first chemically pureergot alkaloid which found widespread thera-peutic use in obstetrics and internal medicine.

The next important step was the discoveryin 1935 of the specific oxytocic principle ofergot by Dudley and Moir, which resulted inthe isolation of the alkaloid ergonovine (alsonamed ergometrine, ergobasine, ergo to cine )simultaneously in four separate laboratories.

Since 1935, extensive investigations on thechemistry of ergot alkaloids have been carriedout, mainly by Jacobs and Craig in the UnitedStates, Smith and Timmis in England, Stoll,Hofmann et al. in Switzerland, paralleled bypharmacological and clinical investigations byRothlin, Cerletti et al. The most importantsteps in these investigations were the following:identification of the common nucleus of allpharmacologically important ergot alkaloids byJacobs and Craig, which they named lysergicacid, in 1934; discovery of iso1ysergic acid by

OHI

C-OH

Smith and Timmis in 1936, isolysergic acidbeing the nucleus of the pharmacologicallyinactive isomers of ergot alkaloids; elucidationof the structure of lysergic and isolysergic acidby Jacobs and Craig and by Stoll, Hofmann andTroxler, which led to the final formula asdepicted in figure 3, published in 1949.

This constitution of lysergic acid andisolysergic acid was confirmed by total syn-thesis by Kornfeld et al. in the Lilly Labora-tories in 1954. A different synthesis of lysergicacid was published by Julia et al. in 1969. Bothsyntheses are only of scientific interest; theycannot compete with the production of lysergicacid from natural sources.

Lysergic acid, possessing two asymmetriccenters, can exist in four stereoisomeric forms:d-Iysergic acid, d-iso1ysergic acid, I-lysergic acidand l-isolysergic acid. With very few exceptions,only the alkaloids or synthetic derivatives con-taining d-1ysergic acid show the high character-istic pharmacological activity.

The first partial synthesis of a natural ergotalkaloid, namely of ergonovine, could berealized by Stoll and Hofmann in 1937, byconnection of lysergic acid in the form of itsreactive azide with L-2-amino-propanol (fig. 4).

CH3I

CO- NH- CH-CH20H

~

' CO-T~~~-jj~~'~\?H•• I •• I N

\ 0 ,~~~J:L --0-'NCH;-----------./ : N.. :

:H ....R2:H L I

HN

Fig. 4. Structure of Ergobasine (syn-onyms Ergonovine, Ergometrine).

R1

H5c200C· .• 1/0BZ'C +ICOCI

s-( +) -alkyl-benzyl-Qxy-ma Lonlc esteracid chLoride

I

Curtiu$

degradation(5 steps)

This method of synthesis was used for thepreparation of a large number of amides ofd-lysergic acid of the type of ergonovine and ofother simple amides which will be discussedlater.

An important discovery, published by Stolland Hofmann in 1943, was the observation thatergotoxine, as described by Barger and Carr in1906, is not a chemical entity, but an ex-tremely variable mixture of three alkaloidswhich we named ergocristine, ergokryptine andergocornine. Later we found that ergokryptineoccurs in two isomeric forms, designated as ():-and {3-ergokryptine.

It was only in 1951 that the completechemical structure of ergotamine and of thealkaloids of the ergotoxine group becameknown. The elucidation of the structure of thepeptide part of these so-called peptide-typealkaloids had taken us many years of chemicaland physicochemical investigations. Figure 5represents the chemical constitution of thepeptide ergot alkaloids, published by Stoll,Hofmann and Petrzilka in 1951.

The constitution of the peptide part, whichis built up by three amino acids, is char-acterized by a so-called cyclol structure, astructural element not known until then inorganic chemistry. The alkaloids of theergotamine and ergotoxine group differ fromeach other by variation of the amino acidradicals. Common to all peptide alkaloids is theamino acid L-proline.

These structures of the peptide type ergotalkaloids were confirmed 10 years later by thetotal synthesis of ergotamine by Hofmann,Frey and OU in 1961 (fig. 6).

Here, in a pharmacological-medical audience,is not the place to discuss the various steps ofthis fascinating piece of synthetic organicchemistry. This would provide the subject of alecture of its own.

The synthetic procedure developed for thesynthesis of ergotamine could be used also forthe synthesis of all other alkaloids of thepeptide type and was worked out by Stadler etal. to a procedure which can be used, and isused today, for the synthetic production ofthese alkaloids on an industrial scale.

After these main achievements of chemicalresearch on ergot alkaloids, I should like tocomplete the picture by discussing briefly someadditional results.

Besides the alkaloids already mentioned, avariety of minor alkaloids have been isolated inour and in other laboratories. Figure 7 providesa survey on the various types of ergotalkaloids.

Whereas the classical ergot alkaloids areamides of lysergic acid, many of the minoralkaloids belong to the so-called clavine type ofergot alkaloids. In this type the carboxyl groupof lysergic acid is reduced to a hydroxymethylor to a methyl group.

Up to the present, some 40 ergot alkaloids,including the isomeric forms, have been isolatedfrom natural sources. Until now, none of theminor alkaloids has found special pharma-cological interest.

Here follow some remarks on new sourcesavailable today for the production of ergotalkaloids. As already mentioned, ergot of ryewas for a long time the only source of thesealkaloids. When the naturally occurring ergotcollected on the rye fields was no longer suf-ficient for the preparation of ergot pharma-ceuticals, methods for artificial inoculation ofrye on an industrial scale were developed firstby Bekesy in Hungary and by Brack in Switzer-land (fig. 8).

Ergot alkatoids

A. Amides of lysergic acid

COR&rH

R1 R2"'-/

CH tf?H, 0 i/ '

&t...CO N_::3---~J-~o

H H R3

NH

R ~ NH2: Ergine

/CH3R ~ NHCH :d·lysergic acid methylcarbinolamide

'OH

.........CH20H

R ~ NHCH :Ergobasin (Ergometrine, Ergonovine), .-CH3

IR•NHC{CH'O:ethergine~

l CH2CH3 J/CH(CH3h

R .• NHCH :d·lysergyl-l·valine·methylester"-COOCH3

R3

CH2C6H5 CH,CH(CH3l:1 CH(CH3)2

IR,.R,-H Ergotamine Ergosine -- Ergotamine group 1IR,.R"CH3 Ergocristine Ergokryptine Ergocornine Ergotoxine group IIR,.HiR"CH3 Ergostine -- -- -- 1

R6}R < CH:~CH3 .

R"HorOH

NH

H-&0/"H

Fig. 7. Survey on the various types of natural ergotalkaloids.

A large percentage of ergot alkaloids usedtoday is still extracted from ergot cultivated onartificially inoculated rye fields. But more andmore important becomes the industrial produc-tion of ergot alkaloids in submerged cultures ofcertain strains of the ergot fungus in tankprocedures. In 1960 Arcamone et al., at the

Agroclavine

Elymoclavine

Penniclavine

'Istituto Superiore di Sanita' in Rome, dis-covered an Italian strain of Claviceps paspaliwhich was able to produce lysergic acid amideand simple derivatives of lysergic acid amide inhigh yield in submerged culture. In 1964,Kobel, Schreier and Rutschmann of the SandozLaboratories succeeded in isolating from ergotgrown on the wild grass Paspalum dilatatum aclaviceps strain capable of producing excellentyields of a mixture of free lysergic acid isomers,

Fig. 8. Artificial inoculation of a rye field with theergot fungus.

mainly paspalic acid, which can easily be trans-formed into lysergic acid (fig. 9). This pmvidesthe possibility to produce lysergic acid on anindustrial scale, in tanks, independent fromergot grown on rye fields. Lysergic acid itselfcan be used then as starting material for thesynthesis on an industrial scale of pharma-ceutical ergot preparations.

The strains of Claviceps purpurea, morerecently discovered in the Sandoz Laboratoriesand by Farmitalia, provide a further source forthe production of medicinally used ergotalkaloids. These strains are able to produce, insubmerged culture, ergot alkaloids of thepeptide type, such as ergotamine or thealkaloids of the ergotoxine group (3).

H, COOH

&?,rn,H

lysergic acid

H COOH

JrH

paspal1c acid

(6-methy 1- 6 8,9 -ergo tene-8-carboxylic acid)

H~ CH20H

~~'H

lysergo 1

Ergometrine(R = CH3)

®Methergine(R= CH2CH3)

Another, quite unexpected source of ergotalkaloids was discovered in 1960 by Hofmannand Tscherter. They found in the old magicMexican drug ololiuqui, which is the Aztecname for the seeds of certain Morning Gloryspecies, lysergic acid amide, lysergic acid-hydroxyethylamide, closely related to lysergicacid diethylamide (LSD), and other lysergicacid derivatives. But this source is only ofphytochemical, not of practical interest.

Chemical Modifications of Natural ErgotAlkaloids and of Synthetic Derivatives withInteresting Pharmacological Activity

Hundreds of chemical modifications andsynthetic variations of ergot alkaloids have beenprepared in our and in other laboratories. Onlythe most important derivatives with interestingpharmacological properties can be discussedhere.

Ergot alkaloids have an astonishingly widespectrum of action, a multiplicity of differentpharmacological activities, such as is rarelyfound in any other group of natural products:peripheral effects on blood vessels and on the

Fig. 10. Modifications in the side chain of ergono-vine (ergometrine).

uterus; neurohumoral effects influencing theaction of adrenaline, serotonin and dopa-minergic structures; central effects on thevasomotor center in the medulla oblongata andon sympathetic centers in the midbrain, parti-cularly in the hypothalamus.

The difference in biological activity of thevarious structural types of ergot alkaloids andderivatives results from the fact that the relativepredominance of these main effects varies fromcompound to compound. One or more of theseactivity components may be almost completelyabsent, other effects may remain unaltered ormay even be enhanced. The goal of chemicalmodifications is to arrive at compounds with anarrower range of activity with more selective,more specific effect.

The first modifications of a natural ergotalkaloid became possible and were carried outafter the development of a partial synthesis ofergonovine, the specific oxytocic factor ofergot, which I have already mentioned. Itprovided the possibility to replace the alka-

nolamine side chain of the natural alkaloid byother amines (fig. 10).

Among the synthetic homologues of er-gonovine, the next higher homologue, i.e., theL-butanolarnide of d-lysergic acid, proved to besuperior in its pharmacological properties to thenatural alkaloid. It is used today worldwidewith the brand name 'Methergine' in obstetricsto stop postpartum hemorrhage.

Within this series of simple synthetic amidesof lysergic acid, I also prepared d-lysergic aciddiethylamide which became famous as a spe-cific, extraordinary potent hallucinogen underthe laboratory code name LSD.

Modifications in the side chain of thepeptide alkaloids by synthetic introduction ofother amino acids than those contained in thenatural alkaloids produced interesting changesin the activity spectrum. Out of the manycompounds of this type synthesized in our

CH20HI

CO-NH- CHH I, CH2-CH3

N- CH3

H

NICH3

l-Methyl-lyserglc aCidL- butanolamlde (UML-491)

Fig. 11. Structural formula of 5' -methyl-ergo-alanine.

Fig. 12. Structural formula of Methysergide.

laboratories only two may be mentioned.Replacing L-phenylalanine in ergotamine bya-methylalanine, a new peptide, called5'-methyl-ergoalanine, was obtained (fig. 11).Compared with ergotamine, its vasoconstrictionpower is 50% higher, while its uterotonic andits emetic activity are many times weaker. Onreplacing L-phenylalanine by O-methyl-L-tyrosine, 5' -p-methoxy ergotamine was ob-tained, which proved to be a specific uterotonicagent.

A very effective chemical modification isalkylation, principally methylation at the posi-tion 1 of the lysergic or dihydrolysergic ringsystem. This leads to compounds withenhanced specific antiserotonin activity. Fromthe large number of I-methyl ergot derivativesstudied as serotonin antagonists, we haveselected for introduction into therapyI-methyl-lysergic acid L-butanolamide (fig. 12).

Generic name: Methysergide. It is used forprophylactic treatment of migraine.

Another I-methyl derivative with similar ac-tivity was described under the laboratory codename MCE by Fregnan and Glasser (fig. 13).

A fundamental change in pharmacologicalactions occurred when the double bond at thepositions 9, lOin the lysergic acid moiety ofthe peptide alkaloids was saturated withhydrogen. The vasoconstrictor and uterotonicactions, the classical effects of ergot, and thestimulation of central sympathetic structures,are greatly attenuated in the dihydro deriva-tives; the activity of the vasomotor center isreduced, whereas the sympathicolytic-adreno-lytic effects are specifically enhanced. Thedihydro derivatives of ergotamine and of thealkaloids of the ergotoxine group, i.e., dihydro-ergocristine, dihydro-ergokryptine anddihydro-ergocornine, which were published byStoll and Hofmann in 1943 and investigatedpharmacologically by Rothlin, Cerletti et al. (4,5) proved to be very interesting pharmaceuticalagents. Dihydro-ergotamine was introducedinto therapy for the treatment of orthostaticdisorders. Dihydro-ergotoxine has become avaluable medicament in geriatrics. New findingsconcerning the pharmacodynamic actions of

R2=~H2 R3;'C~CH CH3 CH3" "-

CH3 CH3

CH3 CH3

o 'CH fPHII 0 'H\ C-NH-t::~ H N

~

N 0 H~~~ 'CH II 3 CH~ ~3~~

HN IBr

Fig. 14. Chemical structures of the dihydro-ergotoxine alkaloids and of 2-bromo-a-ergoiayptine.

dihydro-ergotoxine will play an important rolein the discussions of this meeting.

There would be many other pharmacologi-cally interesting modifications of ergot com-pounds which have been prepared in our and inother laboratories, but time allows me to men-tion only a last ergot modification, which playsalso a role in the discussions of this meeting.This modification consists of the brominationat the position 2 of the lysergic acid molecule.Introduction of halogen, particularly bromine,in lysergic acid derivatives was first publishedby Troxler and Hofmann in 1957.

One of the first bromo-derivatives which weprepared was 2-bromo-LSD. Compared withLSD it showed a quite different activity spec-

trum. The high hallucinogenic activity of LSDhas disappeared. The outstanding pharmacologi-cal property of 2-bromo-LSD is its specificantiserotonin activity.

Another of our many 2-bromo-derivativeswas 2-bromo-a-ergokryptine (fig. 14).

Certain endocrinological effects of peptideergot alkaloids, studied more recently, con-nected with a dopamine agonist action arespecifically enhanced in this compound.

To close my survey I would repeat what Isaid already at the beginning of my talk, thatergot is an extraordinary rich source of valuablepharmaceuticals, which is, as the presentationsof this meeting will prove, still not yetexhausted.

Hofmann, A.: Die Mutterkornalkaloide (Enke,Stuttgart 1964).

2 Stalder, P.A. and Stuetz, P.: The ergot alkaloids; inManske, The alkaloids, vol. 15, pp.I-40 (Aca-demic Press, New York 1975).

3 Kobel, H.: M6glichkeiten zur fermentativen Her-stellung von Mutterkornpeptidalkaloiden. Chern.Rdsch. 27: 57-59 (1974).

4 Rothlin, E.: The pharmacology of the natural anddihydrogenated alkaloids of ergot. Bull. Acad.suisse Sci. med. 2: 1-24 (1946/47).

5 Bircher, R. und Cerletti, A.: PharmakodynamischeGrundlagen der Therapie von Kreislaufst6rungenmit den Dihydroalkaloiden des Mutterkorns. Helv.med. Acta, suppl. 22 (1949).