ergoline alkaloids ergot alkaloids Çavdar mahmuzu alkaloİtlerİ prof. dr. İhsan Çalış

ERGOLINE ALKALOIDSERGOLINE ALKALOIDSERGOT ALKALOIDSERGOT ALKALOIDS

ÇAVDAR MAHMUZU ALKALOİTLERİÇAVDAR MAHMUZU ALKALOİTLERİ

Prof. Dr. İhsan ÇalışProf. Dr. İhsan Çalış

References

• Pharmacognosy:Pharmacognosy: Jean BRUNETON– Phytochemistry, Medicinal PlantsPhytochemistry, Medicinal Plants– Lavosier, 1999 (English Ed.), 2009 (French Ed.)Lavosier, 1999 (English Ed.), 2009 (French Ed.)– Paris, LavosierParis, Lavosier

• Drogen analyse:Drogen analyse: H. Wagner, S. Bladt, E.M. Zgainski

– Springer-Verlag, Berlin, 1983Springer-Verlag, Berlin, 1983

Ergot AlkaloidsErgot Alkaloids• General• Distribution of Alkaloids Derived

from Ergoline• Biosynthetic Origin• Ergot of Rye

– A. The Fungus, the Drag– B. Alkaloid Production

• Field Cultivated Ergot• Industrial Fermentation

– C. Chemical Composition– D. Tests– E. Pharmacological Activity– F. Uses of Ergot Alkaloids Rye Rye

Secale cerealeSecale cerealeÇavdar Çavdar

Ergot AlkaloidsErgot Alkaloids

• Alkaloids in this group are from a – tetracyclic, octahydroindolo-octahydroindolo-quinolinequinoline – nucleus, namely ergolineergoline.

• TThese are commonly classified as hese are commonly classified as – clavinesclavines, – simple lysergic acid derivativessimple lysergic acid derivatives, and – ergopeptinesergopeptines,

N

N

H

2

4

5

67

8

9 10

11

12

13

14

Ergoline nucleus

Ergot AlkaloidsErgot Alkaloids• Ergoline alkaloids Ergoline alkaloids can be substituted at C-8;– by a methyl group (e.g., festuclavinefestuclavine), – or a hydroxymethyl group (e.g.,

dihydrolysergoldihydrolysergol), • 8-Ergolene alkaloids 8-Ergolene alkaloids • can be substituted at C-8 can be substituted at C-8 – by a methyl group (e.g., agroclavineagroclavine), – a hydroxymethyl group (e.g., elymoclavineelymoclavine), – or a carboxyl group (e.g., paspalic acidpaspalic acid).

• Secoergoline alkaloids Secoergoline alkaloids have an open D ring – (e.g., chanoclavine Ichanoclavine I).

N

N

H

2

4

5

67

8

9 10

11

12

13

14

Ergoline nucleus

9-9-ErgolErgoleene alkaloidsne alkaloids


N

N

H

N

N

CH3

H

OR

OH

NH2

N

H

OH

H

H

N

H

H

NCOOH

H

N

N

CH3

H

H

H

N

N

CH3

H

H

H

OH

N

N

CH3

H

H

H

N

N

CH3

H

H

H

OH

O

2

4

5

67

8

9 10

11

12

13

14

Ergoline nucleus

Festuclavine

Lysergic acidand ergopeptines

Norchanoclavine I

Dihydrolysergol

Clavicipitic acids I and II

Agroclavine Paspalic acid

Ergoline alkaloidsErgoline alkaloids 8-8-ErgolErgoleene alkaloidsne alkaloids

RelatedRelated alk alks.s.Secoergoline alkSecoergoline alks.s.


• 9-Ergolene alkaloids 9-Ergolene alkaloids include the the chief alkaloids of the ergot of ryechief alkaloids of the ergot of rye, – whether they have an amino

acid structure • (ergometrineergometrine),

– a peptide structure with a cyclol moiety • (ergopeptines),

– or a peptide structure without a cyclol moiety • (ergopeptams).

N

N

H

N

N

CH3

H

OR

OH

2

4

5

67

8

9 10

11

12

13

14

Ergoline nucleus

Lysergic acidand ergopeptines

DISTRIBUTION OF ALKALOIDS DERIVED FROM DISTRIBUTION OF ALKALOIDS DERIVED FROM ERGOLINEERGOLINE

• These alkaloids were initially characterized in the ergot ergot of ryeof rye, Claviceps purpureaClaviceps purpurea.

• The genus ClavicepsClaviceps comprises about fifty speciesfifty species, and several of them are capable of infesting PoaceaePoaceae, including cereals and non-cereals, and particularly the PaniceaePaniceae.

• ExamplesExamples: C. purpurea on Secale cerealeSecale cereale, • C. paspali on Paspalum Paspalum sppspp., and • C. fusiformis on PennisetumPennisetum. • C. purpurea and C. paspali elaborate mostly

ergopeptinesergopeptines and simple lysergic acid derivativeslysergic acid derivatives, respectively.

• Most of the other ClavicepsClaviceps synthesize clavinesclavines.


DISTRIBUTION OF ALKALOIDS DERIVED FROM DISTRIBUTION OF ALKALOIDS DERIVED FROM ERGOLINEERGOLINE

• The clavinesclavines are also synthesized by other fungi (Aspergillus, Balansia, Penicillium, RhizopusAspergillus, Balansia, Penicillium, Rhizopus) which, in rare cases, elaborate more complex structures (dihydroergosine of Sphacelia sorghi, ergobalansine of Balansia spp.).

• Curiously, certain higher plants are capable of certain higher plants are capable of producing clavinesproducing clavines, simple amides (ergine, hydroxyethylamide), and even ergosine, for example several species in the family ConvolvulaceaeConvolvulaceae, more specifically in the genera Argyreia, Ipomoea, Turbina, Argyreia, Ipomoea, Turbina, and Strictocardia.Strictocardia.


BIOSYNTHETIC ORIGINBIOSYNTHETIC ORIGIN: : TryptophanTryptophan

• Labelling experiments show that the precursors of the precursors of the ergoline nucleusergoline nucleus are tryptophantryptophan, mevalonic acidmevalonic acid, and methioninemethionine: – tryptophantryptophan provides the

indole nucleus, C-4, C-5C-4, C-5, and N-6N-6;

– mevalonic acidmevalonic acid, via dimethylallyl pyrophosphate, is the origin of C-7, -8, -9, -C-7, -8, -9, -1010;

– methioninemethionine (as 5-adenosyl-methionine) methylates N-6.


N

N

CH3

H

O

NH H

N

N

O

R1

OH

O

H OH

ERGOTAMINE

45

6

78

9

10

BIOSYNTHETIC ORIGINBIOSYNTHETIC ORIGIN

• Several mechanisms have been proposed to rationalize the first step in the elaboration of ergoline, in other words the formation of dimethylallyltryptophandimethylallyltryptophan (DMAT).


NH

DMAT

NH2COOH

DDiiMMethylethylAAlyllylTTryptophanryptophanDMATDMAT


• The next step leads to chanoclavinechanoclavine: • DMATDMAT ( (DDiiMMethylethylAAlyllylTTryptophanryptophan))is M-methylated and

decarboxylateddecarboxylated, the methyl group (Z) oxidized to a hydroxy-methyl group hydroxy-methyl group (probably via an epoxide), and the double bond isomerized.


NH

DMAT

NH2COOH

NH

NHCOOH

OH

CH3HN

N

H

Chanoclavine

OH

H

H

CH3


• The next step is the formation of agroclavineagroclavine upon closure of the D ringclosure of the D ring.

• The hydroxymethyl group is oxidized to an aldehyde, which reacts with the secondary amine.


HN

N

H

Chanoclavine

OH

H

H

CH3N

N

CH3

H

H

H

Agroclavine

DD


• Subsequently, a mono-oxygenase induces the hydroxylation of the C-8 methyl group (elymoclavineelymoclavine).


N

N

CH3

H

H

H

Elymoclavine

OH

HN

N

H

Chanoclavine

OH

H

H

CH3N

N

CH3

H

H

H

Agroclavine


• A hypothesis is that peptide alkaloids are formed from the aldaldeehydehyde which arises from the the oxidation of oxidation of the the hydroxymethyl group of elymoclavinehydroxymethyl group of elymoclavine, without going through an acid as an intermediate (lysergic lysergic or paspalic paspalic acidacid).


N

N

CH3

H

H

H

Elymoclavine

OH

N

N

CH3

H

H

H

H

O N

N

CH3

H

OR

OH

N

N

CH3

H

H

H

OH

O

Paspalic acid Lysergic acidand ergopeptines

ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne(Fries) TulasneERGOTISMERGOTISM

• It was around 1000 A.D. that the first precise descriptions of "St. Anthony's fireSt. Anthony's fire" appeared; they referred to ergotismergotism outbreaks, which ravaged western Europe for several centuries .

• ErgotismErgotism, the consequence of the ingestion by humans of the cereals cereals contaminated contaminated by by the the fungusfungus, commonly occurred as one of two forms: – GGangrenous angrenous form form ("St. Anthony's fireSt. Anthony's fire"); the disease began

with a painful inflammation of the extremities, and resulted in numb, blackened, and dry extremities, sometimes ending with their spontaneous loss at a joint;

– CConvulsive onvulsive formform; the dominant Symptoms were mental agitation, delirium, and sensory perturbations.


ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne(Fries) Tulasne

• The prevalence of ergotism decreaseddecreased rapidly as agriculture agriculture improved improved and as nutrition nutrition became became more more diversifieddiversified.

• Ergotism epidemies did take place in the the north north and and the the east of east of Europe Europe until the nineteenth Century , and in the the former former Soviet Soviet Union Union until 1926.

• More recently (1977-78), 47 deaths linked to the ingestion of contaminated cereals were documented in EthiopiaEthiopia.



• The responsibility of bread The responsibility of bread made from infested rye was not suspected until the end of the seventeenth century, and it was not demonstrated in animals until one century later.

• The fungal nature of ergot The fungal nature of ergot was recognized in 17111711, but the mystery of its development cycle was not elucidated until 18531853.

• The twentieth century was to be that of the isolation of the isolation of the alkaloids alkaloids (ergotamine, Stoll, 19181918), of the demonstration of their pharmacological properties, and later, of their mass production by fermentation.

• The oxytocic properties of ergot The oxytocic properties of ergot had long been known (Lonicer, 15821582) and used (pulvis parturiens) before they became reserved for the control of post-partum hemorrhage (this led to a decrease in the number of still births!).


ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea

• The Fungus, the Drug• At first glance, the fungus exists

in two forms: • the vegetative form vegetative form which is a

conidiospore-bearing stroma conidiospore-bearing stroma known as sphaceliasphacelia,

• and the resting form or sclerotiumsclerotium.

• The sphacelia is formed by the mycelium, whose hyphae have invaded the ovary of the rye flower.

• It is at the end of some of the hyphae that the conidiospores develop as the organs of asexual reproduction.


ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea • The Fungus, the Drug• The sclerotium is an elongated, • arched, and purplish black mass, • destined to spend the winter on the ground. • These two forms alternate according to a complex cycle:

• the sexual cyclethe sexual cycle begins in the spring with the formation, on the sclerotium, of masses of stromata on stalks, each containing numerous perithecia, in other words follicles opening by an ostiole and containing the asci.

• The filamentous ascospores released and carried by the wind infect the flowers of other plants. At this point, the mycelium develops into a stroma, which produces the conidiospores;

• the conidiospores, transported by insects, ensure the asexual reproduction of the haploid mycelial gametophyte.



• B. Alkaloid Production• For a long time, the needs of the pharmaceutical industry

were fulfilled exclusively by extraction from sclerotia extraction from sclerotia obtained by artificially infesting ryeartificially infesting rye.

• • Later, it became possible to meet part of the international

demand for active alkaloids by saprophytic culture of saprophytic culture of selected strains selected strains of various species of Claviceps.

• The alkaloids extracted from the culture media were used directly or after chemical transformation (semisynthesissemisynthesis).

• Rehacek and Sajdl (1990) note that: "...the the parasitic culture parasitic culture of ergot of ergot in the in the western hwestern heemisphmispheerere (predominantly Switzerland) has almost stopped".


ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne(Fries) TulasneField Cultivated Ergot (Çavdar Mahmuzu)

• Ergots are obtained by artificial infestation artificial infestation of cereals with strains of the fungus selected for their virulence and their high concentration of alkaloids. This infestation was initially practiced on rye.

• The traditional methodThe traditional method::– First, the selected strain is cultured in a liquid medium with a

composition appropriate for inducing the formation of conidiospores. – At the time of infestation, an inoculum is prepared by suspending the

spores in water (3,000-5,000 spores per mm3). – Next, the inoculum is used to inoculate the young ears (at the latest at

the very beginning of the floration). – The injection is accomplished using Systems resembling hypodermic

syringes connected to a reservoir containing the conidiospore suspension; a specially designed mechanical device brings the ears in contact with the needles.

– The harvest may begin six to seven weeks after inoculation. – The yield of sclerotia is very variable and can reach 300 kg/hectare (=

300 kg/2.47 acres).


ERGOT OF RYE, ERGOT OF RYE, Claviceps Claviceps purpurea purpurea (Fries) Tulasne(Fries) TulasneIndustriaIndustriall Fermentation Fermentation

• The knowledge of how to develop Claviceps on synthetic media is about one hundred years old.

• The different Claviceps can be cultured at pHs near 5.5, which are best adjusted with ammonium salts of the acids of Krebs' cycle (succinate, citrate).

• Frequently, the alkaloid production is dependent on the phosphate concentration of the medium, and for many strains, on the precise concentrations of minerals (iron, zinc, copper, boron) which directly influence the productivity.

• The oxygenation of the culture medium must be intense. Cell differentiation and alkaloid production are controlled by the addition of nutrients: a rich medium causes the formation of abundant hyphal mycelium and no alkaloid production.

• For many strains, it is the phosphate concentration that conditions the passage from the mycelium proliferation phase to the biochemical differentiation phase. Tryptophan, added at the beginning of the fermentation, acts as an enzymatic inducer, and therefore it increases the quantity of alkaloids formed.



• Alkaloids produced• Two approaches are possible: • A. A. The first one consists of producing simple ergolenesproducing simple ergolenes, namely paspalic

acid or the hydroxyethylamide of lysergic acid. • Once isolated from the culture medium, the two ergolene derivatives are

transformed—the first by isomerization, the second by hydrolysis—into lysergic acid, the starting material for the synthesis of non-peptidic alkaloids used in therapeutics (ergometrine and others). – Some clavines can also be the starting materials for the synthesis of more

complex products.• B. B. The second approach, which is more recent, leads to the direct direct

production of ergopeptinesproduction of ergopeptines, particularly ergocryptineergocryptine, from strains of C. purpurea and possibly from other species.

• The fermentation is lengthy, and the ergopeptines are obtained in a yield on the order of g/L. The culture can be directed by adding to the medium the amino acids that are the precursors of the desired tricyclic peptide.



• C. Chemical CompositionC. Chemical Composition::• The ergot of rye is a drug of complex

composition. Besides the sugars and a large number of amino acids, the drug contains a high proportion of lipids: 20 to 40% of its mass consists of an oil which readily turns rancid, hence its degradation in storage. Note also the presence of sterols (ergosterol and related ergosterol and related compoundscompounds), aminesamines arising from the decarboxylation of amino acids, and pigments.



• C. Chemical CompositionC. Chemical Composition• Some are minor and anthraquinone-likeanthraquinone-like (clavorubinclavorubin,

endocrocin), the others are dominant and are mostly xanthone dimers xanthone dimers or ergochromes.

• The concentration of ergoline alkaloids, varies greatly: it might reach 1% in strains intended for the artificial infestation of cereals.


COOH

OH

HO

OH

OOH

O

O

OHOOH

OHH3CO

O

CClavorubinlavorubinMonomeric xanthoneMonomeric xanthone

Alkaloids of Alkaloids of Claviceps purpureaClaviceps purpurea

• TTwo main groups of alkaloidswo main groups of alkaloids are distinguished:

– 1. 1. The simple amides of lysergic acid. The simple amides of lysergic acid. – 2. The ergopeptines2. The ergopeptines


Alkaloids of Alkaloids of Claviceps purpureaClaviceps purpurea 1. 1. The simple amides of lysergic acidThe simple amides of lysergic acid

1. 1. The simple amides of lysergic acidThe simple amides of lysergic acid represent about 20% of the total alkaloids.

• The chief alkaloid in the group is ergonovineergonovine (ergobasine, ergometrineergobasine, ergometrine), the amide of the amide of lysergic acid and of 2-amino-propanollysergic acid and of 2-amino-propanol.

• Ergot also contains a small amount of ergineergine (lysergic acid amidelysergic acid amide).


• 2. 2. The ergopeptinesThe ergopeptines are insoluble in water, are by far the principal alkaloid constituents (80% of the total alkaloids).

• The hydrolysis of ergopeptines affords – lysergic acidlysergic acid, – prolineproline, – ammoniaammonia, – an amino acidamino acid which may be

• phenylalanine, leucine, isoleucine, or valine, and – an αα-ketoacid -ketoacid

• pyruvic acid, dimethylpyruvic acid, α-ketobutyric acid


Alkaloids of Alkaloids of Claviceps purpureaClaviceps purpurea 2. 2. The ergopeptinesThe ergopeptines

• The characteristic structural element of the ergopeptinesergopeptines is the cyclolcyclol formed by the reaction of the hydroxyl group on the α-carbon of an amino acid (that which, by hydrolysis of the peptide, leads to the α-ketoacid), and the carboxyl group of proline.

• The principal alkaloids in this group are ergotamine and "ergotoxine", a mixture of ergocornine, ergocryptine (α + β), and ergocristine.

• The other alkaloids are not abundant and are of no therapeutic interest.


Alkaloids of Alkaloids of Claviceps purpureaClaviceps purpurea 2. 2. The ergopeptinesThe ergopeptines



N

N

CH3

H

O

NH

N

N

O

OH R

O

H OH

ERGOTAMINES

H

N

N

CH3

H

O

NH

N

N

O

OH R

O

H OH

H

N

N

CH3

H

O

NH

N

N

O

OH R

O

H OH

H

ERGOXINES ERGOTOXINES

H H H

AA BB CC

RR A: Ergotamines B: Ergoxines C: Ergotoxines

-CH2C6H5 Ergotamine Ergostine Ergocristine

-CH2CH(CH3)2 α-Ergosine α-Ergoptine α-Ergocryptine

-CH2CH(CH3)2 β-Ergosine - β-Ergocryptine

-CH(CH3)2 Ergovaline Ergonine Ercocornine

-CH2CH3 Ergobine Ergobutine Ergobutyrine



N

N

CH3

H

O

NH

H

H

HO

ERGONOVINE(= Ergometrine)

N

N

CH3

H

O

NH

N

N

O

OHO

H OH

H

ERGOCRISTAM

H

N

N

CH3

H

H

ERGINE

O

H2N

H


• Comment: instability of lysergic acid derivatives.• The derivatives of lysergic acid readily epimerize at C-8 to

form derivatives of isolysergic acid. • This epimerization is enhanced in polar solvents and goes

through an enol intermediate. The nomenclature of the two series differs by the ending of the name of the alkaloid, which is -ine -ine for lysergic acid derivativesfor lysergic acid derivatives, and -inine -inine for the for the corresponding C-8 epimers corresponding C-8 epimers or isolysergic acid derivatives (e.g., ergonovine and ergonovinine, ergosine and ergosinine).

• The chief consequence of epimerization is of a pharmacological nature: the derivatives of isolysergic acid are devoid of activity.



• The aqueous solutions of alkaloids derived from lysergic acid lysergic acid are sensitive to UV radiationsensitive to UV radiation: the photoaddition of a molecule of water across the 8,9-double bond yields stereoisomers.


N

N

CH3

H

H

O

HO N

N

CH3

H

H

OH

HO N

N

CH3

H

H

O

HO

Lysergic acidLysergic acid Isolysergic acidIsolysergic acid

D. TestsD. Tests

• The alkaloids can be detected by color reactions. • The ergot alkaloids react with 4-4-

dimethylaminobenzaldehyde dimethylaminobenzaldehyde under acidic conditions to give a blue color blue color (van Urk reactionvan Urk reaction).

• This color reaction can be used for quantitation (Pharmacopoeia).

• The analysis of complex alkaloid mixtures (total alkaloids, fermentation media, pharmaceutical formulations) can be performed efficiently by HPLC (UV detection).


N

CH3

CH3

O

H

• SS: – AA. Toluol – EtOAc - Diethylamine (70:20:10)– BB. Toluol – Chlororform – EtOH (28,5:57:14,5)

• Detection: Van URK Reagent Van URK Reagent – Van URK Reagent (0.2 g 4-Dimethylaminobenzaldehyde is solved in 25%

HCl adding one drop 10% FeCl3)

Ergot Alkaloids: Ergot Alkaloids: TLC AnalysisTLC Analysis

AA BB

S : S : Secale cornutumSecale cornutumT3 = ErgometrineT3 = ErgometrineT4 = ErgotamineT4 = ErgotamineT5 = ErgocristineT5 = Ergocristine

SSSS

D. TestsD. Tests


M. Ruhland, J. Tischler, M. Ruhland, J. Tischler, Mycotoxin Research Vol. 24, No. 2 (2008), 73-79Mycotoxin Research Vol. 24, No. 2 (2008), 73-79

ERGOTERGOT: : E. Pharmacological Activity

• The pharmacological activity of the ergot alkaloids is particularly complex due to their structural analogy with endogenous amines: noradrenaline, noradrenaline, dopamine, dopamine, and serotonin. serotonin.

• This structural similarity explains the affinity of the alkaloids and their derivatives for the endogenous amine receptors and their ability to exert agonistic or antagonistic effects on those receptorsagonistic or antagonistic effects on those receptors.

• It also explains how, even though these alkaloids may develop a preferred activity on one specific type of receptor (αα-adrenergic, dopaminergic, or -adrenergic, dopaminergic, or serotonergicserotonergic).


Nor-adrenalineNor-adrenaline DopamineDopamine SerotoninSerotonin

OH

N

HHO

OR

H

H

HO

OH

N

OR

H

H

HO

NH

N

OR

H

H

OH

NH2

HO

OH

OH

NH2

HO

OH

NH

NH2HO

Nor-adrenaline

Dopamine

Serotonine

E. Pharmacological ActivityE. Pharmacological Activity

• ErgonovineErgonovine• This alkaloid is a potent oxytocic: it increases basal

tone, and the frequency and strength of uterine contractions; the more advanced the pregnancy, the stronger the effect is.

• This activity is thought to be linked to the stimulation of the αα-adrenergic receptors -adrenergic receptors in the myometrium (uterus kası).

• Uterine hypertonicity Uterine hypertonicity is at the origin of the antihemorrhagic effects of ergonovine. In practice, methylergonovine is the preferred medication.



• E. Pharmacological ActivityE. Pharmacological ActivityErgotamineErgotamine

• At low doses, ergotamineergotamine is a potent vasoconstrictorvasoconstrictor acting by stimulation of the α-adrenergic receptors (or of the serotonergic receptors in the case of the cranial blood vessels). Cranial = Kafatası

• The change in vascular tone is particularly marked peripherally and in the branches of the external carotid; this reaction is accompanied by the closure of the arterio-venous shunts. At higher doses, an adrenergic antagonist activity appears, which is weak, and illustrates the duality in the activities of this compound. In addition, ergotamineergotamine is an oxytocicoxytocic.



• Hydrogenated Derivatives of Naturally-occurring Alkaloids

• 9,10-Dihydroergotamine. 9,10-Dihydroergotamine results from the hydrogenation of the 9,10-double bond, which greatly decreases the agonist activity at the a-adrenergic receptors (the intensity of the activity is thought to be dependent on the preexisting vascular tone) and reinforces the potency of the adrenergic and serotonergic antagonist activity.

• 9,10-Dihydroergotamine is more active on veins than arteries; it is a vasoregulator which "stabilizes vascular tone".



• Hydrogenated Derivatives of Naturally-occurring Alkaloids

• 9,10-Dihydroergotoxine. 9,10-Dihydroergotoxine has a complex pharmacology (stimulation of central receptors, peripheral vasodilation, regulating activity on the neuronal metabolism) which might explain its beneficial effects on what are commonly thought of as behavioral problems due to senile cerebral insufficiency.


Semisynthetic or Synthetic DerivativesSemisynthetic or Synthetic DerivativesErgot AlkaloidsErgot Alkaloids

• Methysergide is a potent serotonergic potent serotonergic antagonistantagonist, devoid of intrinsic vasoconstricting effect. All of its activities (inhibition of the increase in permeability caused by serotonin, decrease of the release of histamine by mastocytes, and more) contribute to making it a basic treatment of migraine headachesbasic treatment of migraine headaches.

N

N

CH3

H

H

O

NH

HHO H

MethysergideMethysergide


• NicergolineNicergoline is a synthetic derivative, more specifically an ester of 10α-methoxylysergol in which the ergoline nucleus is hydroxymethylated at C-8.

• NicergolineNicergoline is pure α-1-adrenergic antagonist, nicergoline is a "cerebral vasodilatorcerebral vasodilator": it increases the arterial blood it increases the arterial blood flow to the brain and enhances glucose and oxygen flow to the brain and enhances glucose and oxygen utilization by brain cellsutilization by brain cells; it also decreases platelet aggregation.

NicergolineNicergoline

N

N

CH3

H

OH

HO

N

Br


• 2-Bromo-2-Bromo-αα-ergocryptine -ergocryptine (= bromocriptinebromocriptine) results from the introduction of a bromine atom bromine atom (Br) (Br) on the carbon atom of indole moiety, and its postsynaptic dopaminergic postsynaptic dopaminergic agonist properties agonist properties are exacerbated (intensified).

• Bromocriptine inhibits the secretion of prolactininhibits the secretion of prolactin..• It compensates the dopamine depletion dopamine depletion due to the

degeneracy of the pathway between the substantia nigra and the corpus striatum in parkinsonismin parkinsonism.

2-Bromo-2-Bromo-αα-ergocriptine-ergocriptine

N

N

CH3

H

O

NH

N

N

O

OHO

H OH

H

H

Br


• LisurideLisuride is a synthetic derivative of the 88αα--aminoergoline typeaminoergoline type.

• Like bromocriptine, it is a dopaminergic agonist dopaminergic agonist with predominant central activity.

• It is also active at serotonergic receptors.

N

N

CH3

H

H

NC

H

N

O

Semisynthetic or Synthetic DerivativesSemisynthetic or Synthetic Derivatives

Lisuride


Semisynthetic or Synthetic DerivativesSemisynthetic or Synthetic Derivatives

• LSD is a semisynthetic derivative, of no use in therapeutics, and it is a potent psychedelicpsychedelic: it is thought to act by interfering with normal serotonergic serotonergic transmissiontransmission.

Lysergic acid diethylamide = Lysergic acid diethylamide = LSDLSD

• Its psychic effects are very marked, and manifest themselves by perceptual changes (shapes, colors, sounds), subjective time alterations, a disintegration of the self, an increase in suggestibility, the resurgence of forgotten memories, and more.

• Physiologically, mydriasis, tachycardia, and tremors are observed, as well as a desynchronization of the electroencephalogram. The environment and the state of mind of the subject (previous experiences, expectations) are determining factors in the onset of undesirable effects: propensity to panic, anxiety, fear of death and insanity, changes in personality, persistence of a psychotic syndrome, and spontaneous recurrence, sometimes for long periods of time, of the psychedelic experience in the absence of further ingestion of the product.

• LSD induces tolerance, but no physical dependence (no withdrawal symptoms)• withdrawal symptoms = yoksunluk sendromu.

N

N

CH3

H

NH

HO

• MethylergometrineMethylergometrine . Methylergometrine maleate is indicated (injectable solution) for obstetric emergencies: afterbirth delivery and post-partum hemorrhages, after cesarean sections, after curettage, after abortion by suction or curettage, and for uterine atony after giving birth.

• The compound must not be used in breast-feeding women. • The blood pressure of patients taking it must be monitored, and side

effects are rare (hypertension attacks).• When it is used by the oral route (solution, tablets), ergometrine is

indicated: – 1. for afterbirth delivery and post-partum hemorrhages post-partum hemorrhages (following

oxytocics administered parenterally); – 2. for metrorrhagia of various origins (after giving birth, therapeutic

abortion, spontaneous abortion); – 3. for the adjunctive treatment of menorrhagia in the absence of

pregnancy after attempts have been made todetermine the cause of the disorder (but for this indication, some feel that the benefit-to-risk ratio is unfavorable).

F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids(natural, modified, semisynthetic, synthetic analogs)(natural, modified, semisynthetic, synthetic analogs)


• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• Ergotamine. Ergotamine tartrate is used orally or rectally, in combination

with caffeine, which accelerates and reinforces its digestive resorption by about 45%.

• This compound provides a specific treatment of the acute attack of migraine headache and related vascular headaches; it must not be considered a basic treatment of the patient with migraines.

• In the majority of cases, the administration of 2 mg is sufficient (in adults) (max 6 mg per day, and in case of multiple doses per week, 10 mg per week).

• If ischemic symptoms appear (vasoconstriction of the extremities, tingling) the treatment must be discontinued immediately.

• Although the risk of ergotism is low, a certain number of pathological conditions increase it, and therefore there are contraindications: occlusive vascular disease, arterial hypertension, coronary insufficiency, and severe hepatic or renal insufficiency.



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• Dihydroergotamine is used for the treatment of migraines and

vascular headaches; to improve the symptoms of venous and lymphatic vessel insufficiency.

• It is also proposed for the treatment of orthostatic hypotension. • The administration on an empty stomach is to be avoided (risk of

nausea). It is best to avoid giving it to pregnant or breast-feeding women.

• First vasoconstrictive phase due to the release of serotonin (scintillating scotoma, tingling, psychic symptoms) and a second phase—the headache—due to vasodilation (decrease in serotonin levels, passive relaxation of the blood vessels).



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• Dihydroergotoxine - dihydroergocristine. Dihydroergotoxine

mesylate is available under various forms designed for oral administration (solution, tablets or single dose lyophilisate, capsules containing microgranules for slow release) and as an injectable solution.

• Also used as a mesylate, dihydroergocristine is commonly combined with an adrenergic antagonist like raubasine (= ajmalicine) or to a substance that will enhance its intestinal absorption (lomifilline).

• These two alkaloids have similar indications: they are proposed for oral administration (2-5 mg/day) as a corrective treatment of senile cerebral insufficiency (lack of attention, memory loss), to treat the sequelae of cerebrovascular accidents, dizziness in the elderly,and retinal disorders of vascular origin.



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• Methysergide . Methysergide maleate is used orally, only in adults (1

mg/day with gradual increase to 4-6 mg/day in France; 2-mg tablets for a usual adult dose of 4-8 mg/day) for the following principal indications: – basic treatment of migrainesmigraines and – facial pain facial pain of vascular origin.

• It is not a treatment for permanent migraine. It is contraindicated in cases of severe hypertension, coronary insufficiency, peripheral vascular symptoms, serious hepatic or renal insufficiency, pregnancy, and breast-feeding. – Continuous administration must not exceed 6 months, and successive

courses of treatment must be separated by 1 month. • Possible side effectsPossible side effects, especially at the beginning of treatment, include

digestive and nervous symptoms (nausea, dizziness, insomnia, or drowsiness).



• F. Uses of Ergot Alkaloids• Nicergoline (INN). Nicergoline (a controlled substance

on French liste II, i.e., a prescription drug), given its a-blocking properties, is indicated for the adjunctive treatment of the intermittent claudication due to chronic occlusive arterial disease of the lower limbs. It is proposed orally or parenterally to improve some of the symptoms of senile cerebral insufficiency (lack of attention, memory loss), or dizziness in the elderly. It is proposed by the parenteral route for acute cerebrovascular accidents of ischemic origin and for the acute manifestations of arteritis of the lower limbs (see above).



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• 2-Bromo-α-ergocryptine (= bromocriptine, INN). There are three main

groups of indications for this substance.

• 1. Prolactin-secreting adenomas: basic treatment; in preparation for surgical procedures in case of macroadenoma; in case of early or late failure following surgery: for the clinical consequences of recurring hyperprolactinemia.

• Clinical consequences of hyperprolactinemia: severe disturbances of the menstrual cycle, sterility, galactorrhea, and in men, gynecomastia (Meme dokusunun büyümesi) and impotence.

• 2. Inhibition of lactation: prevention and inhibition of physiological lactation for

• 3. Treatment of parkinsonism alone (patients over 65 years of age) or in combination with levodopa (to decrease the doses of each drug and delay the onset of fluctuations in efficacy and abnormal movements).



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• The side effects (nausea, vomiting, orthostatic

hypotension) generally disappear fairly rapidly; at high doses and in case of preexisting mental deterioration, psychic symptoms may appear (visual hallucinations, confusion): if they are observed, the posology must be decreased, or the treatment must be discontinued.

• Reports of serious accidents (hypertension, convulsions, cerebrovascular accidents, infarction) have led some countries (United States, Canada) to delete the inhibition of lactation from the indications for bromocriptine.



• F. Uses of Ergot AlkaloidsF. Uses of Ergot Alkaloids• Lisuride. Lisuride. Lisuride maleate has as a chief indication the

treatment of parkinsonism, either in combination with combination with levodopa levodopa early in the treatment.

• The gynecological indications of lisuride are the same as those of bromocriptine (clinical consequences of hyperprolactinemia).

• The side effects are similar to those induced by bromocriptine (nausea, vomiting, orthostatic hypotension, mental confusion, hallucinations, risk of vascular accidents).

• Lysergide Lysergide or LSD 25. The production, marketing, and use of this compound are prohibited.



ergoline alkaloids ergot alkaloids Çavdar mahmuzu alkaloİtlerİ prof. dr. İhsan Çalış

Documents

secoergoline alkaloids

chief alkaloids

ergolinethese alkaloids

mevalonic acid

hydroxymethyl group

paspalic acid

ergoline nucleus

carboxyl group