MorphineMorphine

prof. azaprof. aza

Morphine, Morphine, C17H19NO3, is the C17H19NO3, is the most abundant of most abundant of opium’s 24 alkaloids, opium’s 24 alkaloids, accounting for 9 to accounting for 9 to 14% of opium-extract 14% of opium-extract by mass. Named after by mass. Named after the Roman god of the Roman god of dreams, dreams,

Morpheus, who also became the god of Morpheus, who also became the god of slumber, the drug morphine, appropriately slumber, the drug morphine, appropriately enough, numbs pain, alters mood and enough, numbs pain, alters mood and induces sleep. Less popular and less induces sleep. Less popular and less mentioned effects include nausea, mentioned effects include nausea, vomiting and decreased gastrointestinal vomiting and decreased gastrointestinal motility. (It’s a great constipator, and in motility. (It’s a great constipator, and in Guerin’s painting, Isis is perhaps bringing Guerin’s painting, Isis is perhaps bringing Morpheus a laxative.)Morpheus a laxative.)

Morphine and its related synthetic Morphine and its related synthetic derivatives, known as opioids, are so far derivatives, known as opioids, are so far unbeatable at dulling chronic or so-called unbeatable at dulling chronic or so-called “slow” pain, but unfortunately they are all “slow” pain, but unfortunately they are all physically addictive. During the American physically addictive. During the American Civil War, 400 000 soldiers became Civil War, 400 000 soldiers became addicted to morphine.addicted to morphine.

Both morphine and its hydrated form, C17H19NO3Both morphine and its hydrated form, C17H19NO3..H2O, H2O, are sparingly soluble in water. In five litres of water, only are sparingly soluble in water. In five litres of water, only one gram of the hydrate will dissolve. For this reason, one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulphate and pharmaceutical companies produce sulphate and hydrochloride salts of the drug, both of which are over hydrochloride salts of the drug, both of which are over 300 times more water-soluble than its parent molecule. 300 times more water-soluble than its parent molecule. Whereas the pH of a saturated morphine hydrate Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about from a strong acid but weak base, they are both at about pH = 5; consequently, the morphine salts are mixed with pH = 5; consequently, the morphine salts are mixed with small amounts of NaOH to make them suitable for small amounts of NaOH to make them suitable for injection.injection.      

The three dimensional structure of The three dimensional structure of morphine is fascinating. It consists of five morphine is fascinating. It consists of five rings, three of which are approximately in rings, three of which are approximately in the same plane. The other two rings, the same plane. The other two rings, including the nitrogen one, are each at including the nitrogen one, are each at right angles to the other trio.  (right angles to the other trio.  ( .mol file .mol file ))

OpioidOpioid analgesics analgesics, including morphine, , including morphine, codeine, levorphanol, heroin and codeine, levorphanol, heroin and structurally less similar drugs such as structurally less similar drugs such as meperidine all have an aromatic ring and a meperidine all have an aromatic ring and a quaternary carbon atom linked to a tertiary quaternary carbon atom linked to a tertiary amine group by two other carbon atoms. amine group by two other carbon atoms. This is known as the morphine rule, but it This is known as the morphine rule, but it should be pointed out that all of the should be pointed out that all of the opioids below also have a methyl group opioids below also have a methyl group attached to a nitrogen atom.attached to a nitrogen atom.

Substitute morphine’s methyl group with a propenyl Substitute morphine’s methyl group with a propenyl group, and you create nalorphine, an group, and you create nalorphine, an antagonistantagonist which which counters morphine’s effects. Similarly, hydromorphone, a counters morphine’s effects. Similarly, hydromorphone, a ketone version of morphine five times more powerful ketone version of morphine five times more powerful than its parent molecule becomes the antagonist than its parent molecule becomes the antagonist hydromorphone by the same substitution of a CH3 with a hydromorphone by the same substitution of a CH3 with a CH2CH=CH2 group. More generally, morphine’s b-CH2CH=CH2 group. More generally, morphine’s b-phenylethylamine unit (essentially what I just described phenylethylamine unit (essentially what I just described minus the quaternary carbon atom) is also found at the minus the quaternary carbon atom) is also found at the tail-end of enkephalin molecules. Enkephalins are tail-end of enkephalin molecules. Enkephalins are smaller versions of endorphins, which are produced smaller versions of endorphins, which are produced naturally in the brain, pituitary and other tissues, where naturally in the brain, pituitary and other tissues, where they act very much like opium’s molecules.they act very much like opium’s molecules.   

  

Morphine acts on a specific receptor of nerve Morphine acts on a specific receptor of nerve cells. More specifically many such receptors are cells. More specifically many such receptors are found in the spinal cord’s found in the spinal cord’s substantia gelatinosasubstantia gelatinosa, , a region where pain signals are first processed. a region where pain signals are first processed. The architecture of the morphine receptor is The architecture of the morphine receptor is what dictates the morphine rule. There is a flat what dictates the morphine rule. There is a flat part that binds to the aromatic ring, a cavity that part that binds to the aromatic ring, a cavity that attracts the two carbon atoms and an anionic attracts the two carbon atoms and an anionic site that accommodates the tertiary nitrogen site that accommodates the tertiary nitrogen atom. When morphine or another agonist binds atom. When morphine or another agonist binds to the receptor, the cell membrane’s affinity for to the receptor, the cell membrane’s affinity for sodium ion changes. sodium ion changes.

This eventually reduces the release of This eventually reduces the release of neurotransmitters from the affected neurons. neurotransmitters from the affected neurons. Investigators learned about morphine’s mode of Investigators learned about morphine’s mode of action by applying it and other opiates (including action by applying it and other opiates (including enkephalin) to guinea-pig intestines. (What else enkephalin) to guinea-pig intestines. (What else was gong to serve as the guinea pig for their was gong to serve as the guinea pig for their experiments?) In the presence of antagonists, experiments?) In the presence of antagonists, Na+ affinity was restored and intestinal Na+ affinity was restored and intestinal contractions which had dropped precipitously contractions which had dropped precipitously shot up again.shot up again.

Not all opiates are created equally. Codeine is only 0.1 Not all opiates are created equally. Codeine is only 0.1 % as potent as morphine in binding to receptors. But % as potent as morphine in binding to receptors. But because codeine is converted to morphine by the liver because codeine is converted to morphine by the liver (all that has to happen is that the OCH3 group gets (all that has to happen is that the OCH3 group gets replaced by OH) it becomes 20% as strong as the latter replaced by OH) it becomes 20% as strong as the latter overall. In the late 1800’s, the Bayer company, in hoping overall. In the late 1800’s, the Bayer company, in hoping to come up with a non-addictive pain killer, tried to to come up with a non-addictive pain killer, tried to acetylate both of morphine’s hydroxyl groups.acetylate both of morphine’s hydroxyl groups.

After all, this was in a way similar to how they had After all, this was in a way similar to how they had converted salicylic acid into aspirin. But embarassingly, converted salicylic acid into aspirin. But embarassingly, Bayer invented heroin in the process.Bayer invented heroin in the process.

The 1914 Harrison Narcotics Tax Act in the United The 1914 Harrison Narcotics Tax Act in the United States made possession of morphine a criminal act. States made possession of morphine a criminal act. Forensic scientists exploit aForensic scientists exploit a group characteristic property group characteristic property of morphine and its related compounds: a peculiar of morphine and its related compounds: a peculiar reaction with Mecke's (or Lafon's) reagent. The reagent reaction with Mecke's (or Lafon's) reagent. The reagent consists of selenious acid (H2SeO3)in concentrated consists of selenious acid (H2SeO3)in concentrated sulfuric acid (H2SO4). If morphine and the reagent react, sulfuric acid (H2SO4). If morphine and the reagent react, the following colours appear: green, then quickly a the following colours appear: green, then quickly a greenish blue, changing to blue, next slowly to bluish greenish blue, changing to blue, next slowly to bluish green with a yellow-brown edge, then finally olivaceous green with a yellow-brown edge, then finally olivaceous green. green.

This is one of a variety of color tests that This is one of a variety of color tests that are used. Most, however, are presumptive are used. Most, however, are presumptive tests, meaning that they suggest the tests, meaning that they suggest the presence of opiates but don't absolutely presence of opiates but don't absolutely prove it. Final confirmation is obtained prove it. Final confirmation is obtained through instrumentation, either gas through instrumentation, either gas chromatography-mass-spectrometry or by chromatography-mass-spectrometry or by Fourier Transform Infrared Spectroscopy. Fourier Transform Infrared Spectroscopy. NMR has also been used to identify NMR has also been used to identify heroin. heroin.