Alkaloids Derived from Phenylalanine and Tyrosine

Alkaloids Derived

from Phenylalanine and Tyrosine

İhsan ÇALIŞ

References

R. Hänsel&O. Sticher, Pharmakognosie, Phytopharmazie, Springer, Heidelberg 2007

J. Bruneton, Pharmacognosy: Phytochemistry - Medicinal Plants, Lavosier, Paris 1999, 2009

Alkaloids Derived

from Phenylalanine and Tyrosine

• GENERALITIES

• A very large number of alkaloid structures

arise from the metabolism of aromatic amino acids (phenylalanine, tyrosine).

• These are always isoquinoline alkaloids.

Alkaloids Derived

from Phenylalanine and Tyrosine

• The alkaloids derived from phenylalanine and tyrosine are compounds in which the basic

structural nucleus is an isoquinoline, or far more often,

• a 1,2,3,4-tetrahydroisoquinoline.

NH

NH

COOH HO

HO

NH

COOH HO

N

N

Phenylalanin Fenilalanin

Tyrosin Tirozin

Quinoline Kinolein=Kinolin

isoquinoline

İzokinolein=İzokinolin

Tetrahydroisoquinoline Tetrahidroizokinolin

N H

Alkaloids Derived

from Phenylalanine and Tyrosine

• Biosynthetically, these structures arise from the reaction of the product of decarboxylation of

the amino acid (phenylethylamine, tyramine) or of one of its homologs (dopamine) with another molecule, most often a second molecule of

amino acid which has been deaminated

(aldehyde or equivalent, i.e., an α-ketoacid).

• In rare cases, an isoprene unit may be involved,

for example in Rubiaceae (Psychotria).

Alkaloids Derived

from Phenylalanine and Tyrosine

• Besides the phenethylamines, they are classified under the five main groups as a function of the nature of the precursor(s)

which react(s) with the aromatic amino acid

to form the final structure.

• 1. Simple tetrahidroisoquinoleins

• 2. Benzyl-tetrahidro-isoquinoleins

• 3. Phenethyl-isoquinoleins

• 4. Amaryllidaceae Alkaloids

• 5. Monoterpenoid İsoquinoline alkaloids

Alkaloids Derived

from Phenylalanine and Tyrosine

N isoquinoline

İzokinolein=İzokinolin

3. Phenethyl- isoquinoleins

N N N N

NH₂ (HO)

(HO)

N NH₂

(HO)

COOH

N

N

NH

O

O-Gluc

N

N

N N

O

C₁₀

+ C₆C₂

+ C₆C₃

+ C₆C₁

+ C₁, C₂, or C₅

+ C₆C₂

Phenethylamines

Betalains

Tropolones 4. Amaryllidaceae Alkaloids

1. Simple tetrahidroisoquinoleins

2. Benzyltetrahidroisoquinoleins

5. Monoterpenoid İsoquinoline alkaloids

Main types of iso-

quinoleine alkaloids

Phenylalanine Tyrosine

Alkaloids Derived

from Phenylalanine and Tyrosine

Simple Tetrahydroisoquinoline Alks.

Caryophyllales: Cactaceae, Chenopodiaceae

Benzyltetrahydroisoquinoline Alks.

Magnoliales, Laurales, or Papaverales (Annonaceae, Magnoliaceae, Lauraceae, Monimiaceae, Papaveraceae, Fumariaceae). Ranunculales (Berberidaceae, Menispermaceae, Ranunculaceae), (Euphorbiaceae, Fabaceae).

Phenethylisoquinoline Alks.

Liliaceae (Colchicum)

Alkaloids of the Amaryllidaceae

Clivia, Crinum, Galanthus, Haemanthus, Leucojum, Sternbergia

Monoterpenoid Isoquinoline Alks.

Rubiaceae

1. Simple tetrahidroisoquinoleins

• Pyruvic acid or leucine reacts with the arylalkylamine to form a

1-alkyltetrahydroisoquinoline.

• The reaction with formaldehyde (or its equivalent) leads to a

tetrahydroisoquinoline.

• These compounds are relatively rare, and are found in the

Caryophyllales:

– Cactaceae, Chenopodiaceae, Fabaceae

N

N

N

NH₂ (HO)

(HO)

+ C₁, C₂, or C₅

2. Benzyltetrahydroisoquinoline Alkaloids

• Characterized by a C

C

-N-C

C

nucleus, this is the most

important subgroup from the standpoint of size, and also structural variety and

pharmacological potential.

• The basic nucleus arises from the reaction of the arylalkylamine with a second amino acid,

tyrosine.

NH₂ (HO)

(HO)

N

+ C₆C₂

2. Benzyltetrahydroisoquinoline Alkaloids

• The different alkaloids in this group are

characteristic of a certain number of families of the orders

– Magnoliales, Laurales, or – Papaverales

• Annonaceae, Magnoliaceae, Lauraceae, Monimiaceae, Papaveraceae, Fumariaceae

– Ranunculales

• Berberidaceae, Menispermaceae, Ranunculaceae

3. Phenethylisoquinoline Alkaloids

• A second molecule of aromatic amino acid

participates in the elaboration of a C

C

-N-C

C

nucleus, but this time it is a phenylpropanoic acid

(cinnamic acid).

• These compounds are specific to the Liliaceae

– Androcymbium, Bulbocodium [Colchicum], Gloriosa,

Kreysigia, Schelhammera

NH₂ (HO)

(HO)

N N

O

+ C₆C₃

Tropolones

3. Phenethyl- isoquinoleins

4. Alkaloids of the Amaryllidaceae

• Two aromatic amino acids are required for the formation of the alkaloids;

– one of the two loses one

carbon atom to form a C

C

-N- C

C

nucleus, which only occurs in members of this family,

Amaryllidaceae.

Clivia, Crinum, Galanthus, Haemanthus, Leucojum, Sprekelia, Sternbergia

NH₂ (HO)

(HO)

N

N

+ C₆C₁

AMARYLLIDACEAE ALKALOIDS

Alkaloids

AMARYLLIDACEAE

Galanthus, Pancratium maritumum, Sternbergia

species Activity Studies:

• Cholinesterase inhibitory (acetylcholinesterase and butyrylcholinesterase) and tyrosinase

inhibitory, activities

5. Monoterpenoid Isoquinoline Alkaloids

• A monoterpenoid unit , secologanin, incorporate to the structure, according to a mechanism

resembling the one which leads to monoterpenoid indole alkaloids.

• In fact, they occur in certain species of Rubiaceae.

NH₂ (HO)

(HO)

NH

O

O-Gluc

N

N

C₁₀

+ C₆C₂

Phenethylamines

• Phenethylamine-containing Drugs

– Ephedras:

• Ephedra spp., Ephedraceae

– Khat:

• Catha edulis Forsk., Celastraceae

N

Phenethylamines

• INTRODUCTION

• Phenethylamines occur in many plants. Some are species specific (ephedrine, mescaline,

cathinone) and have marked pharmacological properties, others are common products of the metabolism of aromatic amino acids such as

tyramine or phenylethylamine.

CH₃

NH-CH₃ OH

H H

CH₃ NH₂ H O

NH₂

OCH₃ H₃CO

H₃CO

Ephedrine Cathinone Mescaline

Phenethylamines

• INTRODUCTION

• Although the concentration of these decarboxylation products in edible or medicinal plants is too low to induce harmful effects, it is sometimes sufficient to play a role in the onset of an attack of

migraine.

• The effects of these amines, particularly tyramine, can become serious in patients treated with MAO inhibitors: tyramine is no longer metabolized in the intestine and liver, and a risk of

hypertensive crisis ensues.

• Therefore, it is necessary to monitor the consumption of certain drugs by these patients (e.g., Genista spec.: broom flowers), as well as certain vegetables (avocado, cabbage, cucumber, spinach) and certain other foods (cheese).

PHENETHYLAMINE ALKS.

DRUGS: Ephedras

• Ephedra spp., Ephedraceae

• Although ephedrine is the topic of a monograph in the 3rd

edition of the European

Pharmacopoeia, ephedra has long disappeared from most

pharmacopoeias: only synthetic

ephedrine still finds some uses.

EPHEDRAS

Ephedra spp., Ephedraceae

• The Plants. Ephedras are

dioecious subshrubs with the same habit as horsetails, with slender, angular, and striated branches, and with leaves

reduced to membranous scales.

• The female flowers are reduced to the ovule and surrounded by bracts that are red and fleshy at maturity. The male flowers are grouped in yellowish catkins.

EPHEDRAS

Ephedra spp., Ephedraceae

• The species that contain substantial quantities of alkaloids are mostly Asian:

– E. equisetina & E. sinica Stapf, from China,

– E. intermedia & E. gerardiana, from India and Pakistan.

• About ten species are found in North America, for example Mormon tea, E. nevadensis.

• Ephedras are seldom found in Europe:

– E. major, E. procera, E. campylopoda, or E. distachya of the Atlantic coast.

• Most of these species, except E. major, like the North American species, are thought to contain alkaloids at a negligible concentration or no alkaloids.

TIBBİ BİTKİLER HAKKINDA İLK ESERLER

• M.Ö. 4000

• “PEN TSAO” "herbal" ÇİN İMPARATORU *Chi’en NUNG

– 300’den fazla Bitki Reçetesi

– “ma huang” Chinese Ephedra, Efedrin (izolasyon: 1887)

Astım ve bronşit tedavisinde

kullanılmış en önemli drogtur

Ephedra - Ephedrine

• Ephedra- E. sinica,

known in Chinese as ma huang has been used in traditional Chinese

medicine for 5,000 years for the treatment of

asthma and hay fever, as

well as for the common

cold.

Ephedra - Ephedrine

• Several additional species

belonging to the genus Ephedra have traditionally been used for a variety of medicinal purposes, and are a possible candidate for the Soma plant of Indo-Iranian religion.

• Native Americans and Mormon pioneers drank a tea brewed from an Ephedra, called

Mormon Tea.

Soma (Sanskrit sóma), or Haoma (Avestan), from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater

Persian cultures.

Ephedra nevadensis

EPHEDRAS

Chemical Composition.

• Flavonoids and proanthocyanidins have been identified in the drug, but nitrogen-containing substances—protoalkaloids—

are the focus of attention which are phenethylamine-type derivatives (>2%).

• The main constituent is almost always (-)-ephedrine, which represents from 40 to 90% of the total alkaloids.

• (-)-Ephedrine [= (1R,2S)-l-phenyl-2-methylaminopropan-l-ol]

occurs alongside (+)-pseudoephedrine (which has the 1S,2S configuration) and the corresponding nor and N,N-dimethyl derivatives.

(-)-Ephedrine (+)-Pseudoephedrine

EPHEDRAS,

Ephedra spp., Ephedraceae

• Chemical Composition.

• All of the Asian ephedras contain alkaloids, but their

concentration varies depending on the species: E. sinica (1.3%), E. equisetina (2.2%), E. monosperma (2.8%), E.

intermedia (1.1-1.6%).

• Ephedrine is the major compound in most species, except in

E. intermedia where pseudoephedrine is dominant.

EPHEDRAS,

Ephedra spp., Ephedraceae

• The drug also contains traces of cyclic compounds: 5-phenyloxazolidines and ephedroxane (a 3,4-dimethyl-5-phenyloxazolidone).

• The stems also contain a small amount of an alkaloid derived from

spermidine, namely orantine, whose structure is very closely related to that of the macrocycles described in the subterranean parts of some species in the genus.

• The roots of several species contain an imidazole derivative (feruloyl

histamine), alkaloidal macrocycles derived from spermine (ephedradines A-D), and dimeric flavonoids: bisflavanols (mahuannines) and flavano- flavonols.

Ephedroxane

• Pharmacological Activity.

• Ephedrine is an indirect sympathomimetic.

• Structurally very close to adrenaline, it triggers the release of

sympathetic fibers.

• Ephedrine

– stimulates cardiac automaticity and has a positive inotropic activity;

– accelerates respiration and increases its intensity;

– is a bronchodilator and a stimulant of the brain stem respiration center;

– decreases the contractility of the bladder.

Ephedrine

Pharmacological Activity

Ephedrine

Pharmacological Activity

• Ephedrine

– is not metabolized much, can be used orally, and its duration of action is longer than that of adrenaline.

– is well resorbed and highly lipophilic;

– crosses the blood-brain barrier and, by releasing mediators centrally, has a stimulating psychic effect: stimulation of the attention and ability to

concentrate,

– decrease in the sensation of fatigue and the need for sleep.

• High doses can cause headaches, anxiety, tremors, insomnia, and psychotic manifestations; redness of the face; nausea; tachycardia and precordial pain; sweating; urinary retention, and more.

• Ephedroxane and (+)-pseudoephedrine are experimental anti- inflammatory agents.

USES OF EPHEDRAS,

Ephedra spp., Ephedraceae

• In France, its uses are very limited.

• In Germany, E. sinica can be used by the oral route, but only for a short time.

• In Asia, the drug has been used for about 5 millenia. Mahuang consists of the stems of E. sinica, E. intermedia, and E. equisetina, and is official in the People's Republic of China where it is used as an antiasthmatic, diuretic, and sudorific.

• The Chinese Pharmacopoeia also describes mahuanggen (ephedra root), a drug reputed to be an antisudorific and used as such.

• In the United States, ephedras and ephedrine have been presented for a few years as potential aids in weight loss, a claim based on a hypothetical stimulating action on the combustion of fats.

USES OF EPHEDRAS,

Ephedra spp., Ephedraceae

• Ephedrine can be converted chemically into methcathinone and metamphetamine, two illicit (illegal) substances.

• Naturally, this has led several states in the U.S. to enact restrictive legislation.

• The proliferation of products based on mahuang and/or ephedrine has caused an increase in the number of case reports of more or less serious side effects and in 1997, the FDA proposed detailed labeling requirements for ephedra-based dietary supplements: warnings

against prolonged used and against combinations with products such as caffeine, limited claims, information on side effects, and so forth.

• The directions for using these dietary supplements must not lead the consumer to take more than 8 mg per unit dose and 24 mg/24 hours.

EPHEDRAS,

Ephedra spp., Ephedraceae

• Production of Ephedrine. Although ephedrine can be extracted from Ephedra spp., it is also easy to

synthesize.

• The first step in the synthesis is a biological conversion of benzaldehyde to (R)-1-phenyl-1-hydroxy-2-

propanone by a yeast {Saccharomyces sp.).

• The second step is a treatment with methylamine.

EPHEDRAS: EPHEDRİNE Uses of Ephedrine

• Ephedrine hydrochloride has long been used to treat the acute attack of asthma.

• Its multiple activities,

– numerous contraindications (coronary insufficiency, arterial hypertension, closed angle glaucoma, hyperthyroidism),

– drug interactions (MAO inhibitors, tricyclic antidepressants),

– the required precautions (prostatic hypertrophy, cardiac insufficiency, diabetes), – potential adverse effects (tachycardia, headaches, sweating, agitation, insomnia,

anxiety),

– as well as the fact that the effects wear out if the doses are repeated in close time proximity (tachyphylaxis)

• have led to the virtual (almost) abandon of this compound as a bronchodilator and analeptic.

• However, it remains available in some European countries like France for this indication, particularly in combinations (with theophylline, caffeine, and others).

EPHEDRAS: EPHEDRİNE Uses of Ephedrine

• Ephedrine was formerly used widely for its vasoconstrictive properties, as an ingredient of nasal sprays or nasal drops, for the antiseptic and vasoconstrictive treatment of the acute congestion of rhinitis, sinusitis, and rhinopharyngitis.

• These solutions must not be used in children under three years of age (risk of central excitation symptoms).

• Limiting the use of these solutions to a short time is important, because they can induce iatrogenic rhinitis.

• Ephedrine is also an ingredient of syrups and other formulations designed for the symptomatic treatment of non-productive coughs.

• Note that ephedrine is a banned stimulant in sports, so that its use may result in a positive doping control test.

EPHEDRAS: PSEUDOEPHEDRİNE Uses of Pseudoephedrine

• Pseudoephedrine hydrochloride, alone or in combination (with chlorphenamine, ibuprofen, paracetamol, or triprolidine), is an ingredient of drugs designed for the symptomatic treatment of nasal congestion and rhinorrhea (coryza).

• These products are contraindicated in children and in patients taking MAO inhibitors.

• They must be avoided in pregnant or breast-feeding women.

• They must be used with caution in case of hypertension or urination difficulties.

• Pseudoephedrine has a low toxicity, but it can cause dryness of the mouth,

insomnia, sweating, and anxiety. The onset of tachycardia requires discontinuing the treatment.

• Pseudoephedrine, like its stereoisomer, is a banned stimulant in sport, so that its use may result in a positive doping control test.

• Other Compounds. Combinations of the same type as above contain a synthetic analog of protoalkaloids: norephedrine (= phenypropanolamine).

KHAT

Catha edulis, Celastraceae

• Khat (or cath, chat, jat, tschatt, and so forth) is a shrub of modest size in arid areas (1-2 m), but it can

reach 10 m in the tropics.

• The leaves are highly polymorphic and

indeciduous. Also known as Abyssinian tea, it is native to the horn of Africa (but some think that it originated in

Yemen).

KHAT

Catha edulis, Celastraceae

• Commonly reproduced by vegetative propagation, it is

cultivated in the south-east of the Arabian peninsula (Ta'izz, Yemen), in Somalia, Sudan, Ethiopia

(Harrar), and as far as Kenya

(Meru district) and Madagascar.

• The leaves are harvested from the tip of the branches in the morning and carefully wrapped (banana leaves, damp paper, plastic) for protection against drying and wilting.

Khat in banana leaves

KHAT

Catha edulis Forsk., Celastraceae

• Chemical Composition. Chemically, the leaf contains flavonoids, some essential oil, complex polyesters of

polyhydroxylated dihydroagarofurans (cathedulines), and arylalkylamines (the khatamines), which are responsible for the activity of the drug.

• In the fresh and young leaves, the chief constituent is

cathinone, in other words (S)-α-aminopropiophenone. In the dried drag and in older leaves, this (-)-cathinone has been converted to an 80-20 mixture of (S,S)-(+)-

norpseudoephedrine and (R,S)-(-)-norephedrine.

KHAT

Catha edulis Forsk., Celastraceae

(-)-Kathinon (+)-Norpsödoefedrin (-)-Norefedrin C H ₃

O

N H ₂ H

C H ₃ N H ₂

H H O H

C H ₃ N H ₂

H O H H

C H ₃ O H H

N H ₂ H

C H ₃ N H ₂

H

Merukathin D-Amfetamin

KHAT

Catha edulis Forsk., Celastraceae

• Chemical Composition. Chemically, the leaf contains flavonoids, some essential oil, complex polyesters of polyhydroxylated dihydroagarofurans (cathedulines), and arylalkylamines (the khatamines), which are responsible for the activity of the drug. In the fresh and young leaves, the chief constituent is cathinone, in other words (S)-α-aminopropiophenone. In the dried drag and in older leaves, this (-)-cathinone has been converted to an 80-20 mixture of (S,S)-(+)-

norpseudoephedrine and (R,S)-(-)-norephedrine.

• Fresh drug from northern Kenya also contains the C6-C4 homologs of these

phenylpropylamines: (R,S)-(+)-merucathine, (S)-(+)-merucathinone, and (S,S)-(-)- pseudomeracathine.

• The phenylpropylamine content is maximal in the young shoots and appears to depend on the geographical origin: the cathinone level is reported to range from 9 to 330 mg/100 g depending on the harvest location. A range of variation just as wide has been observed for norephedrine and norpseudoephedrine.

(-)-Kathinon (+)-Norpsödoefedrin (-)-Norefedrin C H ₃

O

N H ₂ H

C H ₃ N H ₂

H H O H

C H ₃ N H ₂

H O H H

C H ₃ O H H

N H ₂ H

C H ₃ N H ₂

H

Merukathin D-Amfetamin

KHAT, CATHA

Catha edulis Forsk., Celastraceae

Drog ayrıca C₆-C₄ homologları olan

merukatin, merukatinon ve pseudomerukatin gibi bileşikleri de taşır.

KHAT

Catha edulis Forsk., Celastraceae

• The cathedulines (Kl, K2, K5,...El-6) are complex molecules whose structure varies as a function of the geographical origin of the drug. Their molecular weight ranges, depending on the acids that esterify the polyhydroxylated sesquiterpene, from 600 to 1,200. Structurally, they are quite close to the

constituents with alkaloid-like behavior that occur in spindle trees and in some species of Maytenus.

KHAT

Catha edulis Forsk., Celastraceae

• Pharmacological Activity - Toxicity. Pharmacologically, the activity of (-)- cathinone is qualitatively quite comparable to that of D-amphetamine: it causes anorexia, hyperthermia, respiratory stimulation, mydriasis,

arrhythmia, and hypertension.

• This amine induces the release of catecholamines from storage. Its effects on the central nervous system depend in part on the subject's environment;

they are characterized by a subjective and euphoric sensation of increased energy, well-being, self-confidence, mental acuity, and ease in thought formation. Objectively, slight euphoria can be observed in a talkative and sometimes hyperactive subject. Later on, undesired effects can appear:

insomnia, nervousness, and nightmares.

• In very rare cases, khat can induce a toxic psychosis, probably by

potentiating a prepsychotic condition. Depression is then observed, and even schizophreniform or paranoid symptoms.

KHAT

Catha edulis Forsk., Celastraceae

• Use of Khat. The fresh leaves, sold within 24 hours of

harvest, constitute a masticatory known for its stimulating properties. In some countries (Yemen), khat use is an

ancient custom and it is practiced at social events,

thereby strengthening social bonds. In other countries, khat is used mainly to seek the pharmacological effects of the alkaloids (to suppress the appetite and to combat

fatigue).

• Traditionally, the leaves (50-200 g) are chewed one by

one, kept in the mouth for a while, then most often spit

out.

KHAT

Catha edulis Forsk., Celastraceae

• In the early 1990s, Brenneisen and El Sohly estimated the number of daily users of khat leaves to be between two and eight million (northeast Africa, Yemen).

• Khat use is officially forbidden in some countries (Saudi Arabia, Sudan, Somalia) and more or less tolerated in other countries.

Tolerated in Yemen where the authorities ban alcohol, khat is thought to be consumed daily by 50% of adult men.

• Cultivated without restriction in Ethiopia, it makes a massive

contribution to the national economy: it is widely consumed

there, and it is also exported to Djibouti where 90% of men and

10% of women are thought to be regular or occasional users.

Isoquinoline Alkaloids

Simple Tetrahydroisoquinolines

• PEYOTE

• Lophophora williamsii – Cactaceae

• Considered a divine plant by the Aztecs, this cactus is a particularly potent hallucinogen. This is the

"plant that makes the eyes

amazed", in other words causes

visual hallucinations, due to the

CNS activity of a phenethylamine

alkaloid, mescaline.

Simple Tetrahydroisoquinolines

PEYOTE: Lophophora williamsii – Cactaceae

• The drug contains a large amount of mucilage and about fifty nitrogen-containing compounds: phenethylamines and

tetrahydroisoquinolines (fresh plant: 0.5-1%, mescal buttons: 6%).

• The phenethylamines include mescaline (= 3,4,5-tri-methoxy- phenethylamine) and its derivatives (N-formyl, N-acetyl, N-

methyl), hordenine, 3-demethyl- and 3,4-demethylmescaline,

tyramine and its derivatives methylated on the nitrogen atom, and dopamine.

• The tetrahydroisoquinoline alkaloids are anhalamine, anhalonidine, anhalidine, pellotine, and lophophorine.

• They arise from the condensation of a phenethylamine with an a- ketoacid (glyoxylic acid, pyruvic acid).

Phenylethylamines and Alkaloids of Peyote

Simple Tetrahydroisoquinolines

PEYOTE: Lophophora williamsii – Cactaceae

• The ingestion of peyote essentially causes psychic effects.

• Mescaline has clinical effects resembling those of LSD (lysergic acid diethylamide): psychic, cognitive, and physical.

– Note in particular a distortion of the perception of shapes, an intensification of colors, auditory hallucinations, and a slowing in the perception of time; the

intensity and the nature of the effects are highly dependent on the environment and the intellect of the subject (for example, his or her artistic sensitivity).

• The physical symptoms that accompany these hallucinations are mydriasis, tachycardia, bradypnea, a sensation of change in

temperature, nausea, and possibly agitation and anxiety. At high doses, memory loss, hypertensive encephalo pathy, and intracranial hemorrhage may be observed.

Isoquinoline Alkaloids

Benzyltetrahydroisoquinolines

• I. Simple Benzylisoquinolines

– Papaverine

• II. Bisbenzyltetrahydroisoquinolines

– Curare

– Other Naturally-occurring Substances with Curare-like Activity

• III. Aporphinoids

• IV. Protoberberines and Derivatives

• V. Morphinan Alkaloids

– Introduction: Biosynthetic Origin – Opium Poppy: Opium

• Chemical Composition

– Opium – Morphine – Codeine

– Other Alkaloids

– Semisynthetic Alkaloids

Isoquinoline Alkaloids

Benzyltetrahydroisoquinolines

• Introduction: The alkaloids derived from 1-

benzylisoquinoline are surpassed, in structural diversity.

• Oxidative Coupling

• The above structural diversity results from the broad reactivity of phenolics, particularly their coupling reactions via radical intermediates:

this is the classic oxidative coupling of phenols.

Isoquinoline Alkaloids

Benzyltetrahydroisoquinolines

• The phenoxy radical, formed upon oxidation of the phenate ion, and stabilized by resonance, is highly reactive: depending on

whether the coupling involves the phenoxy radical and its

mesomers, or only the latter, the result is either the formation of

– a biphenylether bond (Ar-O-Ar), or a

– biphenyl carbon-carbon bond (HO-Ar-Ar-OH).

Formation of the phenoxy radical, mesomerization, Example of

Oxidative

coupling

Isoquinoline Alkaloids

Benzyltetrahydroisoquinolines

• Although this coupling is generally intramolecular, as in the biosynthesis of morphine, aporphinoids, or cularines, it can also be intermolecular: this explains the formation of the

– bisbenzyltetrahydroisoquinoline alkaloids and the – binary aporphine-benzyltetrahydroisoquinoline

alkaloids.

• These coupling reactions are normally followed by

rearomatization (aporphines).

Isoquinoline Alkaloids

Benzyltetrahydroisoquinolines

• In a few cases, however, there is no simple pathway for rearomatization, and rearrangements take place instead, which can lead to new, more or less profound structural variations (morphinan and erythrinane alkaloids).

Alkyl substitution at the coupling site leads to a

rearrangment, after which rearomatization is possible

I. Simple benzylisoquinolines

• The quasi totality of these simple compounds are 1,2,3,4- tetrahydro derivatives, in other words

benzyltetrahydroisoquinolines.

• In a few exceptional cases, they are aromatic: one example is papaverine.

• All of these compounds have, for biogenetic reasons, a 6,7- disubstituted isoquinoline nucleus and a mono-, di-, or trisubstituted benzyl moiety: the most common

derivatives are of the coclaurine type (12-mono-

substituted) and reticuline type (11,12-disubstituted).

• They are the precursors of all other isoquinoline alkaloids.

I. Simple benzylisoquinolines

• Some of these compounds have an interesting

pharmacological potential, for example higenamine

from Annona squamosa and Aconitum japonicum

which is a cardiac stimulant.

BIOSYNTHETIC ORIGIN

• Benzyltetrahydroisoquinolines are pivotal intermediates in the metabolism of isoquinoline alkaloids, and are formed by a

Mannich-type condensation between two metabolites of phenylalanine: for a long time, it was thought that the

condensation of dopamine and 3,4-dihydroxyphenylpyruvic acid led, via norlaudanosoline, to reticuline, a central intermediate in the metabolism of isoquinoline alkaloids.

• The condensation of these two molecules leads to (S)-6-

demethylcoclaurine, which is subsequently methylated (on the 6- position of the phenol and on the nitrogen atom) before being hydroxylated at C-12 and finally, methylated to (5)-reticuline.

BIOSYNTHETIC ORIGIN

Tyrosine

Dopamine

Phenylacetaldehyde

Norcoclaurine

Coclaurine

Reticuline

N-Methylcoclaurine

I. Simple benzylisoquinolines PAPAVERINE

• The spasmolytic activity is more pronounced in the case of a pre-existing spastic condition.

• Papaverine has an effect on the heart muscle: it decreases conductibility and excitability, prolongs the refractory period, and increases coronary blood flow.

• Its activity is linked to its ability to inhibit the phosphodiesterase which

hydrolyzes cAMP, and to decrease the intracellular calcium concentration (by inhibiting its entry into the cell or increasing its uptake by the reticulum).

• Pharmacological Activity.

• Papaverine is a musculotropic spasmolytic which relaxes smooth muscle fibers,

especially those of cerebral, pulmonary, and systemic peripheral blood vessels, but also those of the bronchia, intestines, ureters, and biliary ducts.

N H₃CO

H₃CO

OCH₃ OCH₃

I. Simple benzylisoquinolines PAPAVERINE: Uses

• Uses. It is still fairly widely used as"vasodilator and anti-ischemic" in the curative or preventive treatment of cerebral circulatory

insufficiency.

• In addition to being indicated as a smooth muscle relaxant

(injectable solution at 4%) and for the symptomatic treatment of the intermittent claudication due to chronic occlusive arterial disease of the lower limbs, it is proposed:

– 1. to improve certain symptoms of senility (e.g., loss of attention and memory);

– 2. for the symptoms of ischemia in the eye. It is also used for vertigo in the elderly and to treat the sequelae of cerebrovascular

accidents.

I. Simple benzylisoquinolines PAPAVERINE: Uses

• Uses.

• Contraindications include intra cranial hypertension, parkinsonism, and intracardiac conductibility alterations, but papaverine is not a hypotensive agent and only rarely has side effects (potential tachycardia, constipation, altered transaminases, phosphatases, and bilirubinemia).

• For the same indications as above, papaverine is sometimes combined with other compounds (e.g., butalamine). This alkaloid is also an ingredient of combinations designed to treat capillary fragility (e.g., combinations with hesperidin methyl chalcone, ascorbic acid, and ethoxazorutin).

• As an antispasmodic, it is a component of proprietary drugs designed to relieve the symptoms of functional colopathy, particularly flatulence and diarrhea.