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What I See in the Mirror is Not Me

A chemical tale of lookalikes, side effects, and a nod to the natural.

If you’ve ever had the uber-creepy experience of seeing someone that looked exactly like you, you likely tried to pull out some differences, however subtle. After all, you’re unique, an individual. Molecules have doppelgangers too. They’re called enantiomers, which remind me of some great scenes of Ash in Evil Dead. After all, enantiomers are mirror images of each other, and what’s in the mirror isn’t always friendly.

Enantiomers are a type of stereoisomer. A stereoisomer differs in the spatial arrangement of atoms in a molecule, rather than in the molecular bonds. Enantiomers are driven by something called chirality, which simply means that the mirror-image of a molecule is not super-imposable upon itself. Many molecules have enantiomers, including basic building blocks like amino acids.

It’s well known in the pharmaceutical world that, for many drugs, one of the mirror images or hands of the molecule (left-handed or right-handed) possesses therapeutic properties, and that the mirror images of the drug molecule often show quite different properties. [1] These include non-activity and even potentially adverse effects. [2] If only one isomer is therapeutically active, a 50/50 mix of each means that the drug is half as effective, and one article reported that 50% of marketed drugs are chiral, and 90% of those chiral drugs are marketed as enantiomeric mixtures of racemates. [2] The patenting of a racemic mixture can provide a cushion of market exclusivity to the drug manufacturer due to a process called a “chiral switch”, since the manufacturer of the racemic drug can then re-market as a single enantiomer. [3]

There are multiple ways to report the left- or right-handed nature of molecules. One can choose the +/- notation, which refers to how the molecule rotates polarized light. [3] If the molecule rotates the light to the right, it is given the “+” notation; if to the left, the “– “notation is used. Perhaps more common is the “d” (for dextro) and “l” (for levo) nomenclature for right- and left-handedness, respectively, as in d-limonene. When it comes to delta-9 tetrahydrocannabinol (THC) and its stereoisomers, the left-handed version of the molecule (or (-) notation) is known to be 6 to 100 times stronger than its right-handed (or (+) notation) mirror image. [4] And while the common (-), left-handed version of cannabidiol (CBD) does not bind to cannabinoid (CB) receptors CB1 or CB2, the right-handed (+) version has shown a weak binding affinity to both types of CB receptors. [5]

Enantiomeric terpenoids exist as well, typically with monoterpenes and sesquiterpenes, which are very common in Cannabis sativa. [6] The monoterpene (+)-carvone possesses the aroma of caraway, while the (-)-carvone enantiomer smells like spearmint. (+)-Limonene exudes an orange fragrance, while the (-) enantiomers smells like lemons. [7] The dominance of one of these isomers over the other is what distinguishes the aroma of oranges from lemons. What’s more, the common terpenoid linalool, characteristic of its lavender aroma only exhibits that fragrance for (-)-linalool. The mirror image, (+)-linalool is known to have a citrusy fragrance. [8]

Image Credit: Wikipedia

In this dialogue lies the beauty of and the partition in organic chemistry. The mirror image of a chiral molecule can impart distinguishably different physiological and organoleptic properties. Thus, understanding the stereochemistry of molecules is of importance when designing medicinal products. And this chemical tale exemplifies the interesting and occasionally disturbing notion that what lies in the mirror may be entirely different than you’d expect.

References

[1] Nguyen, L. et al. “Chiral Drugs: An Overview”, Int J Biomed Sci. 2006 Jun; 2(2): 85–100. [journal impact factor = 3.873; cited by 186]

 

[2] Arïes, E.J. “Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology”, European Journal of Clinical Pharmacology, 1984, Volume 26(6): 663–668. [journal impact factor = 2.966; cited by 517]

 

[3] Smith, S. “Chiral Toxicology: It’s the Same Thing…Only Different”, Toxicological Sciences, 2009, Volume 110(1): 4–30. [journal impact factor = 4.081; cited by 214]

 

[4] Dewey W. et al. “Cannabinoid stereoisomers: pharmacological effects”, In: Smith, DF, eds. CRC Handbook of stereoisomers: drugs in psychopharmacology. Boca Raton (FL): CRC Press, 1984: 317-326.

 

[5] Hanus, L. et al. “Enantiomeric cannabidiol derivatives: Synthesis and binding to cannabinoid receptors”, Organic & Biomolecular Chemistry, 2005, Volume 3(6): 1116-23. [journal impact factor = 3.564; cited by 37]

 

[6] Finefield, J. et al. “Enantiomeric Natural Products: Occurrence and Biogenesis”, Angew Chem Int Ed Engl. 2012, Volume 51(20): 4802–4836. [journal impact factor = 12.257; cited by 162]

 

[7] Isac-Garcia, J. et al. “Chapter 7 – Basic Operation Experiments”, Experimental Organic Chemistry Laboratory Manual, 2016, Pages 207-238.

 

[8] Padrayuttawat, A. et al. “Optical Isomers and Odor Thresholds of Volatile Constituents in Citrus sudachi”, Food Sci. Technol. Int. Tokyo, 1997, Volume 3(4): 402-408. [journal impact factor = 1.221; cited by 38]

 

Image Credit: Wikipedia

About the author

Jason S. Lupoi, Ph.D.

Jason S. Lupoi, Ph.D.

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