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Morphine
prof. aza

Morphine,
C17H19NO3, is the
most abundant of
opium’s 24 alkaloids,
accounting for 9 to
14% of opium-extract
by mass. Named after
the Roman god of
dreams,
 Morpheus,
who also became the god of
slumber, the drug morphine, appropriately
enough, numbs pain, alters mood and
induces sleep. Less popular and less
mentioned effects include nausea,
vomiting and decreased gastrointestinal
motility. (It’s a great constipator, and in
Guerin’s painting, Isis is perhaps bringing
Morpheus a laxative.)
 Morphine
and its related synthetic
derivatives, known as opioids, are so far
unbeatable at dulling chronic or so-called
“slow” pain, but unfortunately they are all
physically addictive. During the American
Civil War, 400 000 soldiers became
addicted to morphine.

Both morphine and its hydrated form, C17H19NO3.H2O,
are sparingly soluble in water. In five litres of water, only
one gram of the hydrate will dissolve. For this reason,
pharmaceutical companies produce sulphate and
hydrochloride salts of the drug, both of which are over
300 times more water-soluble than its parent molecule.
Whereas the pH of a saturated morphine hydrate
solution is 8.5, the salts are acidic. Since they derive
from a strong acid but weak base, they are both at about
pH = 5; consequently, the morphine salts are mixed with
small amounts of NaOH to make them suitable for
injection.
 The
three dimensional structure of
morphine is fascinating. It consists of five
rings, three of which are approximately in
the same plane. The other two rings,
including the nitrogen one, are each at
right angles to the other trio. ( .mol file )
 Opioid
analgesics, including morphine,
codeine, levorphanol, heroin and
structurally less similar drugs such as
meperidine all have an aromatic ring and a
quaternary carbon atom linked to a tertiary
amine group by two other carbon atoms.
This is known as the morphine rule, but it
should be pointed out that all of the
opioids below also have a methyl group
attached to a nitrogen atom.


Substitute morphine’s methyl group with a propenyl
group, and you create nalorphine, an antagonist which
counters morphine’s effects. Similarly, hydromorphone, a
ketone version of morphine five times more powerful
than its parent molecule becomes the antagonist
hydromorphone by the same substitution of a CH3 with a
CH2CH=CH2 group. More generally, morphine’s bphenylethylamine unit (essentially what I just described
minus the quaternary carbon atom) is also found at the
tail-end of enkephalin molecules. Enkephalins are
smaller versions of endorphins, which are produced
naturally in the brain, pituitary and other tissues, where
they act very much like opium’s molecules.

Morphine acts on a specific receptor of nerve
cells. More specifically many such receptors are
found in the spinal cord’s substantia gelatinosa,
a region where pain signals are first processed.
The architecture of the morphine receptor is
what dictates the morphine rule. There is a flat
part that binds to the aromatic ring, a cavity that
attracts the two carbon atoms and an anionic
site that accommodates the tertiary nitrogen
atom. When morphine or another agonist binds
to the receptor, the cell membrane’s affinity for
sodium ion changes.

This eventually reduces the release of
neurotransmitters from the affected neurons.
Investigators learned about morphine’s mode of
action by applying it and other opiates (including
enkephalin) to guinea-pig intestines. (What else
was gong to serve as the guinea pig for their
experiments?) In the presence of antagonists,
Na+ affinity was restored and intestinal
contractions which had dropped precipitously
shot up again.


Not all opiates are created equally. Codeine is only 0.1
% as potent as morphine in binding to receptors. But
because codeine is converted to morphine by the liver
(all that has to happen is that the OCH3 group gets
replaced by OH) it becomes 20% as strong as the latter
overall. In the late 1800’s, the Bayer company, in hoping
to come up with a non-addictive pain killer, tried to
acetylate both of morphine’s hydroxyl groups.
After all, this was in a way similar to how they had
converted salicylic acid into aspirin. But embarassingly,
Bayer invented heroin in the process.

The 1914 Harrison Narcotics Tax Act in the United States
made possession of morphine a criminal act. Forensic
scientists exploit a group characteristic property of
morphine and its related compounds: a peculiar reaction
with Mecke's (or Lafon's) reagent. The reagent consists
of selenious acid (H2SeO3)in concentrated sulfuric acid
(H2SO4). If morphine and the reagent react, the
following colours appear: green, then quickly a greenish
blue, changing to blue, next slowly to bluish green with a
yellow-brown edge, then finally olivaceous green.
 This
is one of a variety of color tests that
are used. Most, however, are presumptive
tests, meaning that they suggest the
presence of opiates but don't absolutely
prove it. Final confirmation is obtained
through instrumentation, either gas
chromatography-mass-spectrometry or by
Fourier Transform Infrared Spectroscopy.
NMR has also been used to identify
heroin.