Plants and microorganisms produce over 150,000 natural molecules, some of which are bioactive in humans. I am writing this post in response to the wave of celebrity deaths, some of which may be attributed to drug overdoses.
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| Figure 1: Opium poppy (Papaver somniferum) courtesy of the DEA Museum website |
The opium poppy is the source of morphine and codeine. Hydrocodone (e.g., Vicodin) is a semi-synthetic opioid synthesized from codeine. According to the US DEA, hydrocodone is the most frequently prescribed opioid in the
United States and is associated with more drug abuse and
diversion than any other licit or illicit opioid. Dextromethorphan (pronounced "dex-tro-meth-orphan") is a molecule that resulted from a search for a non-addictive analogue of codeine that still retained cough relief. Unfortunately, it still carries a risk for abuse.
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| Figure 2: Most widely used (and abused) opioids |
This year, the musician Prince is said to have died from a fentanyl overdose. A structurally similar molecule, demerol, is primarily used in labor and delivery. Demerol was the first wholly synthetic opioid developed, in 1939. Fentanyl was discovered in 1960 by screening demerol analogues. To my eyes, it isn't easy to see the structural similarity between the plant-based opioids (natural and semi-synthetic) and the synthetic opioids.
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| Figure 3: Red region of the molecules mimics the endogenous ligand for opioid receptor, a GPCR |
There are multiple types of opioid receptors: mu (MOR), delta (DOR), and kappa (KOR) among them. The drugs mentioned here mimic the endogenous morphine, also known as endorphin. There are multiple types of endorphin peptides, but one endorphin peptide met-enkephalin (structure not shown) shares a common substructure with the plant-based opioids (shown in red in Figure 3).
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| Figure 4: Selectivity of opioids for three classes of opioid receptors |
Different opioids have varying degrees of selectivity for the different classes of opioid receptors. This selectivity may explain why distinct substructures can have a similar effect.
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| Figure 5: A set of structurally related anti-diarrheal compounds in current use |
Orienting the fentanyl molecule differently reveals its structural similarity to other anti-diarrheals, Immodium and the combination drug called Limodil. A side effect of opioids is constipation. Everything I know about opioid abuse, I learned from the movie Trainspotting.
References:
"Drug Discovery and Development, Volume 2: Drug Development" Mukund S. Chorghade, Ed.
John Wiley & Sons, 2007.
Chahl, Loris A. "Opioids - mechanisms of action" Australian Prescriber, 1996.
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