Download Morphine - ISpatula

Lecture 14
Remember
the principal opium alkaloids (Morphine, Codeine, thebaine) are considered as
Modified Benzyltetrahydroisoquinoline Alkaloids.
Last lecture we were discussing the different opium alkaloids and there
therapeutic proprieties. Now we will discuss in more details:
Codeine:
*in fact, it is the most widely therapeutically used opium alkaloids (main
representative).
* antitussive and mild analgesic agent.
*it is 3-O methyl morphine.
*it can be metabolized partially by liver enzymes (de-methylated) to produce
morphine so it produces morphine-like analgesic effects but little euphoria.
*it's about one –tenth (1/10) the potency of morphine.
So, relatively it is a safe non-addictive medium analgesic –for sure- when
used within the therapeutic doses, if exceeded or used for a prolong period of
time there will be -definitely- dependence, addiction and also constipation.
Thebaine:
*in fact, thebaine hasn’t introduced to the therapeutic utilization,-instead- it
has been considered as a one of the most important raw materials used in the
production of other morphinan drugs such as morphine, codeine and semisynthetic opiates.
*Nowadays, some countries cultivate a genetically modified papaver somniferum
which produce thebaine as a major constituent rather than morphine and
codeine.
Why??
To overcome obtaining direct morphine which can be easily converted to heroine
It is a way to restrict the misusing of opium alkaloids.
*One of the countries which -restrictly- cultivates this modified papaver
somniferum is Australia, it doesn't produce morphine or codeine as major
constituents anymore instead all morphinan alkaloids are based on thebaine
production which is semi-synthetically demethylated to any of them, only
according to the demands .
Papaverine :
*papaverine itself is an ingredient of crude opium (opium alkaloids) but it is
not a morphinan alkaloid.
*structurally, it is not a benzyltetrahydroisoquinoline but it is a benzylisoquinoline since it possess a double bond in the heterocycle.
Note: tetrahydros are the first saturated compounds which are then
dehydrogenated to the unsaturated froms.
Morphinan alkaloids are thebaine, codeine and morphine only.
*It has no analgesic or hypnotic properties, but it relaxes smooth muscle in
blood vessel and as a spasmolytic agent.
* Until the discovery of the oral sildenafil (ViagraR), it has been used as an
effective treatment for male impotence, being administered by direct injection.
Nowadays, this use is neglected.
Noscapine (narcotine in the past):
*very potent antitussive agent comparable to codeine.
* Despite many years of use as an antitussive, the finding that noscapine may
have teratogenic properties (i.e. may deform a fetus) has resulted in noscapine
preparations being deleted.
* It has no analgesic or narcotic action so its original name ‘narcotine’ was
changed to reflect this lack of narcotic action.
*based on the fact that all toxic substances are investigated for their
antitumor activity, it has been found that noscapine is possessing this activity
in a similar mechanism to that of colchicine antimitosis.
But because of the teratogenicity, it is still unsafe for this purpose.
 Recent studies are held in order to decrease this teratogenicity and increase
the antimitotic activity by the production of possible semi-synthetic derivatives
of noscapine.
*So far the previous discussed compounds are pure entities  that’s means
most of opium alkaloids are used as purified single compounds (rather than a
mixture of them) in form of their primary hydrochlorides.
Ex: morphine available in injections as morphine hydrochloride (soluble form).
But always there is an exception!
Papaveretum:
* A mixture of purified opium alkaloids, as their hydrochlorides, with morphine
as a major constituent 86% , codeine (7.8%) and papaverine (6.7%).
* It is used for pain relief during operations and it is usually enriched with
anticholinergic activity by the addition of hyoscine then used with hospitalized
patients.
Morphine (in details):
*morphine is metabolized in our body form to glucoronides which are readily
excreted.
In fact, theoretically we have 2 –OHs in the structure of morphine at
positions (3 and 6) so we can form: morphine-3-glucoronide, morphine-6glucoronide or morphine-3,6- diglucoronides.
* But what has been found in our bodies that morphine-3-glucoronide
metabolite is not very stable as morphine-6-glucoronide, the bond between the
aglycon and the sugar part (glucoronic acid) can be easily breaked down during
metabolism.
So, morphine is eliminated from our bodies in form of morphine-6glucoronide.
Interesting point:
*Scientists isolate this metabolite (morphine-6-glucoronide) and by analysis it
has been found that it possesses a very potent analgetic activity even more
potent than morphine itself.
Accordingly, morphine-6-glucoronide has been prepared semi-synthetically to
be used with terminal cancer patients since it is significantly hydrolysed in the
gut; it is much less effective taken orally than when administered by injection.
*Among the morphinan alkaloids we have 2 acidic compounds (exceptional):
1-Narceine which possess a carboxyl group.
2-morphine which is considering as an acidic compound although it has a N.
this acidity is related to the presence of a phenolic –OH in its structure.
Why this is important?
This acidity will facilitate the isolation of morphine from crude opium
alkaloids extract.
Morphine biosynthesis:
*among the (aromatic amino acids derived alkaloids) we have started with
phenylalanine alone or tyrosine alone in the biosynthesis of some alkaloids,
others, as in the case of colchicines we have started with both of them.
In our opium alkaloids we will start with 2 molecules of tyrosine and the
pathway of each molecule is different.
1-the first tyrosine molecule as we have seen in the previous lectures will be
carboxylated to tyronine which is further hyroxylated to dopamine.
Tyrosine 
*Now in order to form a benzyltetrahydoisoquinoline (which opium alkaloids are
belonging to) we need an activated C#1 for this cyclization and formation of
this benzyltetrahydroisoquinoline structure  this C#1 initiation can done by a
carbonyl group (formaldehyde, acetaldehyde …etc) the source of this carbonyl
is the second tyrosine molecule.
2-the second tyrosine molecule will be transaminated (losing amino group)but
gaining a carbonyl group.
The resulted compound is 4-hydroxyphenyl pyruvic acid which is further
decarboxylated to the active aldehyde.
3- Condensation of hydroxyphenyl acetaldehyde and dopamine to yield the first
benzyltetrahydroisoquinoline.
C#1
C#1
Note:
From the structure above we can notice that the deference between simple
tetrahydroisoquinolines and benzyltetrahydroisoquinoline is that C#1 in the later
attached to a benzyl rather than a methyl as in tetrahydroisoquinolines which
characterized by anhalamine.
4- Carbon #1 in benzyltetrahydroisoquinoline is very imp since it is a chiral
center but what does this mean??
In fact our first benzyltetrahydroisoquinoline (norcoclaurine above) is
belonging to the S series since the alpha shaded H at C#1, but morphinan
alkaloids are derivatives of the R series, the question is rising now: how the
conversion occurs?
It is a unique reaction in the nature, that’s means if prepared in the lab
scientists obtain a racemic mixture of both stereoisomers S and R not one of
them alone.
To understand how conversion occurs lets go back to the compound which we
stop with (norcoclaurine):
S-norcoclaurine (-nor indicate no methyl at the N) is methylated to Scoclaurine.
S-coclaurine has 2 possible pathways:
1-further methylated to (S)-N-methylcoclaurine then 3' hydroxylation and
methylation at C#4' to obtain S-reticuline.
or
2-oxygenation of C# 3' and further methylation at C#4' into S-nor –reticuline
,then the remaining hydroxyls are methylated followed by dehydrogenation of
the heterocyclic ring to obtain papaverine.
so papaverine is one of the constituents that is found in the opium.
Going back to S-reticuline which is our interest we have to mention that it
can be also obtained by simple methylation of S-nor-reticuline.
Now, S-reticuline which is obtained by either ways is an important intermediate
but still S- series and we need the R one, Nature do it!
Nature makes small tricks to do it,
First it polishes the stereochemistry by simple 1-2 dehydrogenation and creating
a double bond with a N-cation, followed by other reduction done by a highly
specific enzyme (only found in certain plants), but this time the formed
reticuline is belonging to the R series 
Then R-reticuline will be converted to the other morphinan alkaloids in
papaver somniferum specie or thebaine in the genetically modified one.
Q:
Why morphinan alkaloids are the major constituents compared to papverine??
Because when S-coclaurine entered different pathways and converted to
different compounds part of them can converted to papaverine while all of
them can be converted to S-reticuline and so morphinan alkaloids.
Comparing the structures of R-reticuline and the resultant morphinan
alkaloids we will recognize unusual thing:
The cyclohexan ring which is originated from tyrosine is upside down and the
aromatic part of the benzyl group is coming up in the morphine structure fo
example so what happened!!
Again it is the nature, the molecule turning around itself or clapping 180
degrees so the benzyl group will be on the upper part of the molecule,
continues clapping but this time diagonal turn will led us to this final form of
morphine.
When this turning mechanism finalized, the formation of ether linkage occur
with elimination of water molecule and thebaine is formed, further
demethylation give us codeine and morphine.
*in genetically modified papaver somniferum demethylation is blocked to end up
with thebaine.
Synthetic and semi-synthetic derivatives of morphine (the key compound):
Minor modifications in the structure may lead to massive changes in the
biological activities we can emphasize some, delete the other.
What are these modifications?
1-codeine can be reduced and converted to dihydro-codeine which is a very
potent analgetic compound.
2-morphine also can be reduced then the alcoholic –OH can be oxidized to a
carbonyl to obtain hydromorphone which is more analgetic but 4 sure more
adverse effects.
3-morphine also can be alkylated using its phenolic –OH to form pholcodeine
possessing antitussive activity similar to that of codeine.
4-morphine can be demethylated simply to nor-morphine and many substances
have been produced by alkylation of this demethylated nitrogen.
 One of them is bearing an allyl group and found to be as one of the first
series of substances which classified as morphine-agonist-anatgonist (substances
possessing analgetic activity but antagonize the adverse effects of morphine
they are essential to overcome morphine adverse reactions specially symptoms
of overdose and addiction …etc) this compound is called Nalorphine.
5- In the early days of the 20th century scientists decide to produce a safer
analgetic derivative than morphine since it was causing many problems such as
euphoria and other adverse effects.
They acetylated the 2 –OHs of morphine to achieve this purpose and produce
(heroine), very shortly it has been found that heroine is much more potent
than morphine and more lipophilic since it possessing 2 acetyls which make it
effective orally, parentally and other routes of administration.
But also this diacetyl-morphine (heroine) is more addictive and smaller doses
can lead to euphoria (if it has been taken 4 2 weeks, tolerance occurs and
addiction develops.
*apomorphine:
*Obtained by heating morphine in the presence of acid which lead to a
completely changed structure (ex; the ether linkage is eliminated)
*has no analgesic properties, but morphine’s side-effects of nausea and vomiting
are highly emphasized.
*is a powerful emetic and can be injected for emergency treatment of
poisoning (differs from other emetics in being parentally rather than orally).
Synthetic derivatives:
* Dextromethorphan:
*One of the most widely used morphine analogues in the therapeutic purposes.
*potent antitussive agent.
*in lab preparations we obtain both isomers: dextromethorphan and
levomethorphan but it has been found that dextromethorphan is lacking the
analgetic activity with potentiated antitussive activity. While levomethorphan is
possessing analgetic and antitussive activities.
In fact, since this combination is not requested, dextromethorphan alone is
the preferred drug material, being completely non-addictive.
Now, the other synthetic derivatives of morphine which we will discuss now,
all are possessing analgetic activity differing in their duration of action …etc
* Pentazocine:
* Structurally, a morphine-like structure where the ether bridge has been
omitted and the cyclohexene ring has been replaced by simple methyl group and
the N-methyl is replaced by aliphatic chain.
* Pentazocine has both agonist and antagonist properties, and although it is a
good analgesic, it can induce withdrawal symptoms.
Note: all synthetic cpds do possess CNS euphoria addiction and tolerance.
Pethidine (meperidine):
*very simple in structure (because it has been found in order to produce a
morphine-like-activity in the human brain the requirements are aromatic ring
and piperidine system possessing a chiral center).
* Short-acting, quick and short-duration analgesia, used nowadays as a pain killer
parentally in surgery.
Tramadol:
* is a recent drug firstly synthesized in 1980 as an analgetic , it wasn't causing
addiction but recent studies show that tolerance can be developed.
The drug in no more used.
Methadone:
*Methadone is orally active, has similar activity to morphine, but is less
euphorigenic and has a longer duration of action. Although it is as potentially
addictive as morphine, the withdrawal symptoms are different and much less
severe than with other drugs such as heroin, so that methadone and
Buprenorphine (a semi-synthetic derivative of thebaine) are widely used for the
treatment and rehabilitation of heroin addicts.
Ex: withdrawal symptoms with methadone don’t appear before 48 hours but in
morphine or heroine a second urgent dose needed within the next 24 hours.
Note:
Thebaine in addition to its use as a raw material for the production of other
morphinan alkaloids is now the raw material for semi-synthesis of several useful
drugs such as oxymorphone, which are potent analgesics.
oxymorphone can also act as a raw material that undergo further processing
to produce morphine-agonist-antagonist or pure antagonists. (So thebaine can
produce substances that counteract the effects of morphine and heroine).
Example on these semi-synthetics derivatives of thebaine:
*Naloxone and Naltrexone are pure antagonists.
* nalbuphine is a mixed agonist-antagonist.
Finally:
We have to mention other semi-synthetic compound derived from thebaine
which is etorphine.
*it is about more than 1000 times as potent as morphine and it is only used
4 animal sedation.
*it is not misused because it is not designed 4 human use.
The end
Done by :Hadeel Damra