Download The amino acid Tyrosine

Medicinal Plants – Sheet #26
Amino Alkaloids
In the last lecture, we started to discuss Derivatives of aromatic amino acids ;
Phenylalanine & Tyrosine. And we classified these alkaloids as Alkaloidal amines
( Amino Alkaloids ) ,because :1) The nitrogen is not a part of the heterocyclic ring.
2) The nitrogen is originating from a Trans-amination reaction.
The Phenylalkylamines
They are subclassified depending on the number of carbons of the side chain.
Either we'll have Capsaicinoids ,or Benzylamine derivatives, or Phenylethylamine
derivatives, or β-amino-phenylpropane derivatives.
Phenylethylamine derivatives
Already it's a very indicating name : There's an aromatic ring and the side chain ;
an ethyl amine (with 2 carbons & amino group )
and here we are talking again about the precursors Phenylalanine & Tyrosine.
In fact, both amino acids proceed into two important reactions :1) Decarboxylation : to obtain corresponding amines.
2) Modification :
What are the modifications?!
a) Hydroxylation (oxidation ) on the aromatic ring .
b) Hydroxylation( oxidation ) of side chain.
c) Methylation .
These are basically important reactions to obtain different closely related
phenylethylamine derivatives .
The amino acid Tyrosine
para-hydroxyphenylalanine, it can be easily decarboxylated to its biogenic amine
: Tyramine.
1
It's in fact with this chapter ,we are entering a very important chapter of the
pharmacology ( the chapter of Catecholamines )
Catecholamines
They are important neurotransmitters of the mammalian organisms ,and they
are derivatives of this group of amino acids ( Amino acid derivatives ). Obtained
by the simple reactions mentioned above :
a) Hydroxylation (oxidation ) on the aromatic ring .
b) Hydroxylation( oxidation ) of side chain.
c) Methylation
And these Catecholamines are : Adrenaline (Epinephrine), Noradrenaline
(Norepinephrine) ,& Dopamine.
There are many plants containing Adrenaline , Noradrenaline,& Dopamine ,but
as plant constituents of less importance because of their instability in GIT of
humans.
Catecholamines should be administered parenterally (injection ) in order to
observe their activity.
And when we talk about plant constituents ,our primary objective is to use these
plants as such after drying in form of infusion or in form of a Tea .
Isolation from the plant ; when we are using the pure isolated compounds then
there's no difference from the synthetic compounds. it follows the single entity
regulations ,like the cardiac glycoside Digoxin .
but as plant constituents ,if we them in form of simple preparations ,then we are
talking about Herpal Remedies.
Therefore, because of their instability in GIT ,none of these catecholamines are of
plant constituents of interest, unless we use these plants as a source of more
economical production of these compounds.
so we cannot use them to benefit as a Tea of Epinephrine or such.
But, there are other drug constituents structurally closely related to these
substances ,and stable in the GIT ; a Phenylethylamine derivative : Mescaline .
Mescalin
2
A phenyethylamine derivative; 3,4,5-trimethoxyphenethylamine ( as a
representative of GI stable derivative ).
It's the active principal obtained from the cactus Lophophora williamsii (
Cactaceae ) .
These cacti are growing mainly in Southern America and Northern Mexico.
And they became famous because the American Indians or the old inhabitants of
Mexico were using these plants in a dry form or in form of a tea as a means of
inducing hallucinations during religious ceremonies.
The crude drug is called " Mescal Buttons "; Flattened-shaped button-like
outgrowths on the stem of the cactus ,so they were taking either these mescal
buttons or they were making slices (transversal cuts) then they were drying them
and taking them in the mouth ( ingestion ) ,or in the form of a tea .
As a result of this ,they were experiencing certain hallucinations ,and they were
aiming to have these hallucinations in order to get a better connection with their
Gods (to become nearer to their Gods) when they were mentally ,somehow ,
exciting from the normal performance and entering in an outside world; a
transient world ; or an imaginary world .
Hallucinations were accompanied primarily by visual symptoms; observing
flashing lights ,bright colors (colored hallucinations) , distortion of the shapes ( or
objects of their surroundings taking different shapes ), and they were hearing
non-existing music & sounds.
Mescaline is classified as one of the three important psychedelic agents ,these
are :1) Mescaline ( Natural )
2) Psilocybin ( Natural )
3) LSD ( Semi-synthetic ) - Lysergic acid Diethylamide : The most famous & the
most potent among the three.
The first two are not used commonly ,even in the experimental psychiatry
,because LSD has superseded them.
What is the Mescaline structurally ?
It's as we have seen in Adrenaline , Noradrenaline , & dopamine with a difference;
that there's a third hydroxylation in the aromatic part , and none of the hydroxyl
groups are occurring in the free form ; they are possessing methyl groups.
Mescaline can be synthesized from tyrosine or a hydroxylated
phenylalanine,which is decarboxylated to tyramine then followed by oxidation (
3
Hydroxylation) to dopamine. Dopamine converts into mescaline in a biosynthetic
pathway involving m-O-methylation and aromatic hydroxylation.
so, it's a very structurally simple compound with buzzard effect on the mood of
human-beings (Hallucinations).
But, again, it's not a wide spread misused drug ( it's not used worldwide ).
 β-amino-phenylpropane derivatives
Indicating the β position of the amino carbon on the side chain
Most important derivative of this this group : Ephedrine
Ephedrine
A β-amino-phenylpropane derivative; 2-(methylamino)-1-phenylpropan-1-ol ,
which has adrenaline-like activities ( sympatho-mimetic ), but ephedrine is orallyactive ,and with longer duration of action than adrenaline.
It's obtained from Ephedra sinica ( Ephedraceae) and other related species.
It's one of the eldest medicinally reported plants.
E.sinica comes from China, has been used in traditional Chinese medicine for
thousands of years under the name " ma huang "
It was primarily used in the treatment of common cold ,but it's now claimed for
its vasoconstriction activity and possibilities to be used as a vasoconstrictor in
the treatment of rhinitis , and for its bronchodilator activity in the treatment of
allergic asthma.
Ephedrine and ephedrine based compounds are banned by FDA, In response to
accumulating evidence of adverse effects and deaths related to ephedra.
It's accompanied in the plant with its stereoisomer Pseudoephedrine , and
pseudoephedrine is used for its vasoconstriction activity ( α-adrenergic activity )
in the treatment of rhinitis . And all products based on ephedrine and
pseudoephedrine are banned from the Sport activities ,classified as a Doping
agent (The use of performance-enhancing drugs in human sport is commonly
referred to by the term doping )
In fact, until the late 70's ,ephedra preparations were widely used in weightreducing tablets;due to their activity on the fat consumption ,but nowadays it's
not permitted to use either ephedrine or pseudoephedrine in the weight-reducing
preparations ,because they get the user a mild high ,these plant products are
classified as "Uppers" ,so they are considered as "Ecstacy" ( entactogenic
/psychoactive) ; because they have amphetamine-like activity.
4
Structure & Correlation of Ephedra alkaloids
Alkaloids do not occur in a single form . In the plant, we always have major
alkaloids & minor alkaloids ( (1)Major + (n) Minor ) , so mainly the major
alkaloid is accompanied with a number of minor alkaloids ,therefore, when we
say ephedrine and pseudoephedrine, then we'll expect there are other closelyrelated alkaloids that are occurring in the ephedra species ,and they have
correlations with one another.
Epherda alkaloids are derivatives of the amino acids ; phenylalanine ( mainly) &
tyrosine ,but the amino acid is not donating the nitrogen . The nitrogen is
intorduced by a Trans-amination reaction.
Different intermediates are converted into the Diketone ; the occurrence of the
diketone is an essential intermediate in the biosynthetic pathway ,otherwise,we
cannot continue with the trans-amination reaction.
And as as a result of the transamination ,we obtain a basic intermaediate termed
the Cathinone, that still possesses one of the carbonyl groups as a keto group,
and the other keto group has already changed versus the amino group.
Now, the next reaction is the Reduction ,the carbonyl group can be reduced
,then we obtain two isomeric compounds : Norephedrine &
Norpseudoephedrine.
* The prefix "nor-" indicates that there must be a closely-related compound with
an additional methyl (it indicates either a nor-methyl or a nor-methoxy)
So, when we say : norephedrine & norpseudoephedrine, then there must be
methylated derivatives ,and these methylated derivatives are : Ephedrine &
Pseudoephedrine.
Further methylation of this amino group ( there's still a hydrogen that can be
replaced with another methyl group ) will obtain :From ephedrine : N-methylephedrine.
& From pseudoephedrine : N-methylpseudoephedrine.
These substances ( Ephedrine & Pseudoephedrine ) have similar activities to that
of Amphetamine . Also basic similarities to the structure of Amphetamine but the
absence of hydroxyl group . There's also methamphetamine ; one of the
hydrogens is methylated .
Important Note
5
Norpseudoephedrine is also termed as "Cathine" , Structurally the same.
( Different researchers were working on Ephedra species and others on Catha
edulis ( Khat Tea ). Those working on Catha edulis isolated compound which
they termed as " Cathine " and those working on Ephedra species isolated the
same compound and termed it as "Norpseudoephedrine". So, two different
reserchers isolated the same compound ,named differently ).
Therefore, when we say "Khat leaves " ,we don't say it contains
Norpseudoephedrine , we say it contains Cathine .
But ,in fact, Cathine is structurally nothing else than Norpseudoephedrine.
Khat or Abyssinian Tea
Alkaloids found in the Khat are very closely-related to Ephedra alkaloids ,and
there are other secondary metabolites.
It's the leaf of Catha edulis ( Celastraceae ); a small tree which is cultivated in
Yemen, Somalia , and Ethiopia .
It's the primary plant for misused leaves of this tea.
The active principals are found in the leaves.
The major active compound is Cathinone ( not Cathine ).
It's preferred to use the cut leaves when they are young leaves ( why ?! )
Because during their development, the cathinone is reduced to cathine and
norehedrine. So, in the young leaves ,the major constituent is Cathinone , and
this ketone is the major active principal and has the major biological activity of
the cut leaves ( when we use older leaves ,we isolate cathine ).
*In general, It's rich in alkaloids.
* It contains complex alkaloids called Cathedulins.
*There are also flavonoids , tannins , volatile oils ...etc. ( rich in secondary
metabolites ).
* The effect of Cathinone is similar to that of Amphetamine.
Khat is classified in some countries of the Arabic world as a Social drug like in
Yemen. It's forbidden in Saudi Arabia . Black-listed in Soudan and Somalia .
It's not internationally used widely.
The misuse is restricted to Arabic World ; this is easily explained because the
activity is best observed in young fresh leaves ,which means if they want to
6
transfer the leaves from Yemen ( for example ) to the States or Europe, then there
will be complicated procedures, while the majority of other hallucinogenic
preparations like marihuana are already used as dried material. So, it's not wide
spread throughout the world like other addicted drugs.
* When young leaves are kept in banana leaves ,they keep their freshness for 24
hours.
* Usually , the leaves should be used within the first 24 hours of preparation.
* It's classified in Yemen as a Social drug ; because it increase the self-confidence
,talkativeness, and alertness of the users . But main activity is suppression the
feeling of hunger , therefore , Anorexia is one of the adverse effects seen in
individuals who are using these leaves for long term. Inflammation of the oral
cavity is common. The plant also contains tannins constipation is a common
observation as a side effect .
* By chewing the leaves , the user will have a Constant mild high
* Long-term use is associated with impotency & female infertility .
Colchicine
Another class of derivatives of Penylalanine & Tyrosine .
Obtained from Colchicum autumnale ( Liliaceae ).
This is a small class of secondary metabolites and observed only primarily in two
families : Amaryllidaceae & Liliaceae .
Colchicine is representing the family Liliaceae as a derivative of the different
alkaloids which are originating from Phenylalanine & Tyrosine.
Colchicine is pharmacologically an important drug., available in the market (
Colchicine tablets are available in the Jordanian market ) ,and it's used primarily
for the control of Acute attacks of Gout.
Note : Ingredient of Colchicine table is natural ,not synthetic.
Colchicine isolated as a pure compound either from the seeds or from the tuberlike underground parts of the plant Colchicum autumnale , so seeds and corms
are collected ,submitted to extraction , and then Colchicine is obtained .
It's not only Colchicine in the plant , there's also Demecolcine and other related
alkaloids .
7
Biosynthesis of Colchicine
Biosynthesis of Colchicine is one the most complex biosynthetic pathways ,
because it includes both amino acids together ( both Phenylalanine & Tyrosine ),
but each amino acid has a different pathway
* Phenylalanine proceeds in Shikimic acid pathway, it will be dis-aminated ( lose
the amino group ) and then formation of the shikimic acid ( Cinnamic acid ; C6C3 derivatives )
* While Tyrosine will be decarboxylated and converted to its biogenic amine :
Tyramine , and the nitrogen of Tyramine is incorporated in the structure of
colchicine ( The nitrogen atom in Colchicine is Tyrosine-derived ).
So, in the biosynthesis of Colchicine ,there's no trans-amination reaction.
Structure of Colchicine
It has an aromatic ring ( ring A ) , a 7-membered ring ( ring B ) , a tropolone ring (
ring C ) ; whis is a pseudo-aromatic 7-membered ring ).
Biosynthetically , ring A is derived from Phenylalanine ,which also contributes
carbon atoms 5,6,and 7 of ring B , while the rest is originating from the amino
acid Tyrosine.
Colchicine is not a true alkaloid because nitrogen is not part of the heterocyclic
ring, it's on the side chain .
There's an amide group ( nitrogen is part of the amide function ) , and its
presence indicates that Colchicine is non-basic neutral alkaloid.
*Colchicine has a potent anti-inflammatory activity .
* It's a cytotoxic agent ( Anti-tumor agent ) : But until now ,neither colchicine nor
any semi-synthetic derivative of colchicine is utilized pharmacologically as antitumor agent, it's nit used because of its toxicity ; the cytotoxicity is affecting the
cancerous cells and the normal cells ( non-selective toxicity ) , so it's not used
despite its very potent anti-mitotic activity .
* Colchicine is highly poisonous , it's used in Europe primarily as a suicidal
agent.
Note
To study the structures , please refer to the slides.
Good Luck
Made by : Haneen M. Elayyan & Alaa Safadi.
8