Indol alkaloids

Indole Alkaloids ErgotErgot

Prof.as. Najim abbas Al awwadi

B.Sc., M.Sc., DEA., Ph.D. Pharmacology

Paris. France

Indole Alkaloids1- Ergot Alkaloids

• Occurrence:Ergot is the dried sclerotium of a fungus, Claviceps purpurea (Fam. Hypocreacea) that arise on the ovaries of the rye plant (Secale cereale, Fam. Gramineae).

• Consumption of flour contaminated with Ergot led to many serious intoxications known as (Ergotism- Ignis Fire) in Europe.

• Ergot can be detected in flour by using UV light where contaminated flour will show violet spots.

1630…fed to 1630…fed to animals (all died)animals (all died)

1909…tyramine 1909…tyramine 1910…histamine1910…histamine

1884…calmodulin 1884…calmodulin alkaloidalkaloid

1906-1918…1906-1918…ergotoxine ergotoxine

and and ergotamineergotamine

History of Clinical History of Clinical TrialsTrials

The Ergot The Ergot AlkaloidsAlkaloids

• • Structure based on indole ringStructure based on indole ring• • Starting amino acid is tryptophanStarting amino acid is tryptophan• • All ergot alkaloids are derivatives of All ergot alkaloids are derivatives of (+)-Lysergic Acid(+)-Lysergic Acid

INDOLE DERIVATIVESe.g. :

1. ergometrine,2. ergotamine,3. reserpine,4. vincristine,5. vinblastine

• Classification of Ergot Alkaloids:

A- Clavine Type Alkaloids:Simple water soluble bases with little medicinal value. All end with “clavine: e.g. Agroclavine.

B- Lysergic acid Amides:They are all derivatives of (l)-Lysergic acid and subclassified into:

1- Simple lysergic acid amides:Composed of Lysergic acid and simple amines.

2- Polypeptide Alkaloids:Composed of Lysergic acid and at least 3 amino acids.

• General Characters: Ergot alkaloids are N-monosubstituted amide derivatives of both lysergic

acid and its isomer isolysergic acid that differ only in configuration at C-8. On treatment with ammonia, lysergic and isolysergic acids give the

corresponding amides ergine and isoergine respectively.

Members related to lysergic acid (e.g. ergotamine and ergometrine) are levorotatory, more active and designated by suffix “ine”.

Members related to isolysergic acid (e.g. ergotaminine and ergometrinine), are dextrorotatory, less active and designated by suffix “inine”.

NH

N CH3

COOH

10

8

NH

N CH3

COOH

NH

N CH3

CONH2

Lysergic acid Isolysergic acid Ergine

1- Simple Lysergic acid amides• Characters:

1- Composed of Lysergic acid and simple amines.2- Low molecular weight.

3- Water Soluble.

Ergonovine (Ergometrine)

Composed of (l)-lysergic acid and 2-aminopropanol. Its (d) isomer is called Ergometrinine.

• Uses:It causes vigorous contraction of the uterus. It is mainly used as an oxytocic in order to aid delivery or to prevent postpartum hemorrhage.

NH

N CH3

COHNHCH2C

10

8

CH3OH

Ergonovine (l) (Ergometrine)Ergonovinine (d) (Ergometrinine)

==

Lysergic acid diethylamide (LSD) It is a semisynthetic product. LSD has potent CNS stimulant effect. LSD is one of the abused drugs.

NH

N CH3

CON

10

8

C2H5

C2H5

2- Polypeptide Alkaloids• Characters:

They are derivatives of Lysergic acid with a complex polypeptides of at least 3 amino acids.

They have high molecular weight.

They are insoluble in water.

This class include medicinally important members.

Ergotamine• Characters: Its (d) isomer is called Ergotaminine. The peptide moiety is composed of 3 amino acids:1. -Hydroxyalanine2. Proline3. Phenylalanine

• Uses:Treatment of migraine as it constricts the peripheral blood vessels.Has some oxytocic (ecobolic) activity.

NH

N CH3

COO

N

NOH

CH3

CH2O

O

10

89

Structure Activity Relationship: Lysergic acid must be in the (l) form. The (d) isomers are

inactive. Saturation of the 9- 10 double bond of Ergotamine gives

Dihydroergotamine, a compound with antimigraine effect but no oxytocic effect.

NH

N CH3

COO

N

NOH

CH3

CH2O

O

10

89

Stability:• The active (l) form convert to the (d) isomer by the effect of

Alkalis or prolonged storage in alcohol.

• Addition of water to the 9- 10 double bond takes place in aqueous acidic solutions, upon exposure to day or UV light. The resulted Lumi alkaloids are inactive.

N CH3

C

O

N CH3

C

N CH3

C

O

10

8

10

8

10

8H H

R RRHO

(l) form (d) form

N CH3

C

O

10

8H

R

HO

• Tests for identification:

Van-Urk's Reagent (p-dimethyl aminobenzaldehyde (PDAB) in 15% H2SO4, containing traces of FeCl3) + Alkaloid → Deep blue color.

Erlich Reagent (p-dimethyl aminobenzaldehyde (PDAB) in H2SO4) + Alkaloid → Deep blue colour.

Keller’s test: Solution of the alkaloids in acetic acid with traces of FeCl3 + concentrated H2SO4 on the wall of the test tube → blue layer is formed between the two phases.

General General Biosynthesis of Biosynthesis of

AlkaloidsAlkaloids

Important DerivativesImportant DerivativesNatural Products:Natural Products:

ErgonovineErgonovineErgotamineErgotamine

Semisynthetic Semisynthetic Products:Products:

Methylergonovine maleateMethylergonovine maleateDihydroergotamine mesylateDihydroergotamine mesylateLysergic acid diethylamineLysergic acid diethylamine

Synthetic Products:Synthetic Products:sumatriptan (Imitrexsumatriptan (Imitrex®)®)

Peripheral Effects• smooth muscle contractionssmooth muscle contractions

• Cures migraine headachesCures migraine headaches• lowers blood pressurelowers blood pressure

• extracts usedextracts used•Ergotamine tartrate + caffeineErgotamine tartrate + caffeine•dihydroergotaminedihydroergotamine

Uterotonic Effects

•childbirthchildbirth•accelerate childbirthaccelerate childbirth•arrest hemorrhagingarrest hemorrhaging

•Extracts usedExtracts used•ergonovine maleateergonovine maleate•ergometrineergometrine•ergotamine (prolonged effects)ergotamine (prolonged effects)

Neurohormonal Effects

Serotonin antagonism•ExtractExtract

•methysergidemethysergide

•TreatmentsTreatments•prophylaxis for migraineprophylaxis for migraine•carciniod syndromecarciniod syndrome•rhuematic affectionsrhuematic affections

Neurohormonal Effects

Adrenergic blockade•TreatmentsTreatments•high blood pressurehigh blood pressure•cerebral circulatory disorderscerebral circulatory disorders•vascular disordersvascular disorders•cervical syndromecervical syndrome•Extracts usedExtracts used

•dihydroergocorninedihydroergocornine•dihydroergokryptinedihydroergokryptine•dihydroergocristinedihydroergocristine

Central EffectsBulbomedullary effects

•EffectsEffects•bradycardiabradycardia•vomitingvomiting•inhibition of vasomotor centerinhibition of vasomotor center•inhibition of pressoreceptor reflexesinhibition of pressoreceptor reflexes

•ExtractsExtracts•ergot alkaloids aloneergot alkaloids alone•(has sedative effect)(has sedative effect)

Central EffectsMesodrencephalic effects•EffectsEffects

•hyperthermiahyperthermia•hyperglycemiahyperglycemia•mydriasismydriasis•piloerectionpiloerection•tachypneatachypnea•hyperreflexiahyperreflexia•general motorgeneral motor•hyperactivityhyperactivity •ExtractExtract

•lysergidelysergide