The Right Chemistry: Reflecting on mirror-image molecules



Some items, like pairs of gloves or shoes, actually exist as non-superimposable mirror images. So do some molecules.

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Everything has a mirror image, save perhaps a vampire. Place a spoon in front of a mirror and imagine that somehow you were able to reach into the mirror and pick up its mirror image. If you now compare the two items, they would be identical. Now imagine taking a glove off your left hand and placing that in front of a mirror. If you were able to pick up the mirror image, you would find that it fits the right hand, not the left. If you superimposed one on the other, the thumbs would point in opposite directions. What we have are non-superimposable mirror images! What is the criterion for this property? A lack of symmetry! Any item that is symmetrical will be identical to its mirror image, while items that lack symmetry will have a non-superimposable mirror image. Some items, like pairs of gloves or shoes, actually exist as non-superimposable mirror images. So do some molecules.

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The commercial synthesis of the popular pain reliever ibuprofen (Advil, Motrin), yields two non-superimposable mirror image forms, commonly referred to as “enantiomers.” It turns out that only one of the two has biological activity, not an unusual phenomenon for reactions that occur in the body. Often molecules have to engage with enzymes or fit into receptors on cells, both of which require interaction with proteins that are “chiral” or have “handedness.” One enantiomer will fit, like a left glove fitting the left hand. The other will be like trying to put a left glove on the right hand. With ibuprofen, the inactive version is harmless, so the medication is sold as a mixture of the two enantiomers, known as a racemic mixture.

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In some instances, such as with Dopa, the drug that is widely used to treat Parkinson’s disease, only one enantiomer is converted in the body to dopamine, the molecule that is in short supply in the disease. The other enantiomer is not only useless, but gives rise to serious side effects. In this case, it is important to be able to produce only the active form, known as L-Dopa, which can be done by so-called asymmetric synthesis. William Knowles shared the 2001 Nobel Prize in Chemistry for developing this process.

Sometimes marketing rather than efficacy drives the introduction of a single enantiomer drug. The anti-ulcer medication omeprazole (Prilosec, Losec) made a fortune for its manufacturer AstraZeneca but it was set to go off patent in 2001. How to beat off competition from generics that were expected to flood the market? AstraZeneca came up with a plan. Omeprazole is a chiral drug, but in this case, both enantiomers are active, so historically it was marketed as a racemic mixture. If one enantiomer could be shown to be somehow preferable, it could be marketed as a new drug and receive patent protection. Some clever data mining revealed that one enantiomer, christened esomeprazole, was broken down a touch more slowly in the body. This was enough to obtain a patent and esomeprazole went on the market as Nexium. This meant that half as much Nexium would have the same efficacy as the usual dose of omeprazole, which was 40 mg. But AstraZeneca recommended Nexium also at 40 mg, so people naturally did feel more relief. Critics argued that the same result can be had from just doubling the dose of racemic omeprazole, at a fraction of the cost. Nexium turned out to be a big win for AstraZeneca, but not necessarily for the public.

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Now there is an interesting story emerging with another chiral drug, ketamine, a widely used anesthetic and pain killer that also has been found to have an antidepressant effect. Although there has been no formal approval for its use as an antidepressant, physicians have been prescribing it “off-label” to patients who were not helped with the standard medications such as the serotonin reuptake inhibitors (SSRIs). Since ketamine is an older drug and is off patent, there has been no motivation for pharmaceutical companies to fund studies about its antidepressant effect. At least not until recently when Janssen pharmaceuticals decided to explore the possibility that one of the ketamine enantiomers may have superior efficacy. The single enantiomer could then be marketed as a novel drug and receive patent protection.

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The first challenge was to either develop a synthetic process yielding only the single enantiomer, or to find a means of separating the components of the racemic mixture. The latter turned out to be more practical. A technique known as “chiral liquid chromatography” involves introducing a racemic mixture into a column packed with a material that has chiral properties, commonly a modified version of amylose, a type of starch. As the mixture is propelled through the column by a solvent, one of the enantiomers will stick to the packing material more than the other and a separation can be achieved. In this case, esketamine can be separated from arketamine.

Janssen’s trials showed that esketamine is effective for “treatment resistant depression” and managed to get FDA and Health Canada approval for Spravator, a nasally administered version. However, there was no direct comparison with generic, racemic ketamine, and expert opinions differ on whether Spravator is worth the extra expense, which is considerable.

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About five per cent of adults suffer from depression, a leading cause of disability worldwide, and about 30 per cent of cases are “treatment resistant,” meaning that they have not responded to at least two antidepressant medications. If Spravator does turn out to be truly effective, it would be yet another triumph for chemistry and a welcome treatment for victims of depression. Only time will tell.

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Joe Schwarcz is director of McGill University’s Office for Science & Society ( He hosts The Dr. Joe Show on CJAD Radio 800 AM every Sunday from 3 to 4 p.m.

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