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Pain chemistry: part 2

Watch David discuss the chemical structure of morphine and the interactions it makes with the opioid receptor.
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DAVID MANALLACK: The interaction between a drug and a protein can be likened to a key fitting a lock. In the case of morphine, the molecule, like a key, is rigid, giving us clues about the required shape needed for pain drugs that work as opiates. Before we look at the protein target of morphine, the opioid receptor, we will review the functional groups on morphine that are needed for pain relief. There are five important functional groups in morphine that we will focus on. The first of these functional groups is a hydroxyl group. And morphine has two of these groups, as shown here. The oxygen, with a hydrogen attached, has the ability to form interactions with proteins, as well as improve solubility.
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Ring A is an aromatic ring, or a benzene ring. This ring is flat and provides further structural rigidity.
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The basic nitrogen atom makes a key interaction with the receptor. And interestingly, this group becomes positively charged when it enters our bloodstream. Finally, the oxygen in ring E makes the link between the A and C rings, tying it together. Having identified the important chemical groups, let’s look at some of the interactions these groups make with the opioid receptor that we mentioned earlier. This animation will show a series of important interactions that morphine makes with the receptor protein. The first is a salt bridge between an aspartic acid and the amino group of morphine.
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The second interaction is between a tyrosine and the ether oxygen of morphine, known as a hydrogen bond.
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Finally, we show two hydrophobic interactions between an isoleucine and methionine, shown by wavy lines, with the A ring of morphine.
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Here, we see all four interactions that are made with our molecule.
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We will now look at morphine in the context of the entire receptor protein. Here, we have placed morphine into the protein and give it a shape-filled representation.
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We can now see the seven helices of our GPCR. And we’re colouring each of those with a different colour.
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As we rotate it round, we see where morphine is placed within the protein. And if we look at this end-on, we can see that morphine fits into a beautiful cavity within the receptor protein.
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Before we review this chemistry module, it would be useful to reflect on the presence of opioid receptors in the brain. The fact that morphine works as an analgesic is wonderfully accidental. The human body produces its own pain relieving chemicals, known as enkephalins. And if you’d like to learn more about the enkephalins, there is an optional activity we’ve developed on these compounds in this course. So let’s review what we’ve seen in this chemistry module. Our detailed look at morphine explored the structure of this substance, highlighting the five rings, its key functional groups, and the overall shape of the molecule.
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We examined three of the interactions in detail, with the opioid receptor, and used molecular animations to show these interactions in more detail. Finally, we showed the binding location of morphine within the receptor.

Watch David discuss the chemical structure of morphine and the interactions it makes with the opioid receptor.

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The Science of Medicines

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