By David Warmflash
Earlier this year, the Scripps Research Institute introduced a new, extremely effective method for making drugs selective to chirality. This will be a milestone in a pharmaceutical world that’s growing ever more cognizant of the impact of drug stereochemistry, the 3-dimensional orientation of asymmetric, or chiral, carbon atoms. This happens because a carbon atom can form four single covalent bonds, oriented in a tetrahedral pattern from its nucleus. When four different kinds of atoms attach to a carbon atom in this way, two different structures, called enantiomers, are possible, and their shapes are opposite in the same sense as your left and right hands. This is vital to pharmacology because the enzymes, cell receptors, and other complex biological molecules that drugs target contain numerous asymmetric carbons, and often so do the drugs.
Physiological Consequences of Chirality
Just as a glove designed for the left hand will not fit very well on the right, enantiomers of molecules introduced to the body often fit differently with cell receptors. Orange peel and lemon peel both get their citric smell and taste from limonene, for instance, which exists in two enantiomeric forms. Called R-limonene and S-limonene respectively, these two enantiomers cannot be superimposed on one another, just as your hands cannot be superimposed. Since the chemical receptors in your mouth and nose also have asymmetric carbons, they respond differently to the two compounds. R-limonene has a slightly richer, fuller taste of an orange, whereas S-limonene has a more pungent, minty characteristic.
You may prefer one citric fruit over another, but consequences of chirality are more profound when it comes to drugs. The classic anti-muscarinic drug atropine is a racemic mixture of two enantiomers, l- and d-hyoscyamine. Both enantiomers are competitive inhibitors of muscarinic acetylcholine receptors. The l-enantiomer is more powerful in terms of the desired effect and the side effects, so there is no major drawback to a racemic mixture, but the story can be very different for some other drugs.
The Lesson of Thalidomide
R-thalidomide, for example, is an effective sedative, anxiolytic, and anti-cancer drug. It also works well against the nausea associated with pregnancy, with minimal side effects. So when put to market the late 1950s, thalidomide was hailed as a miracle drug. It didn’t turn out that way, however, because the S-enantiomer is a teratogen. It deletes and shortens appendages in developing fetuses. The significance of drug chirality was unappreciated back then, so when thalidomide shifted from research to mass production, it was produced as a racemic mixture.
Consequently, there was an epidemic of horrible birth defects, and thalidomide was pulled from the market in Europe and other places where it was in wide use, often without a prescription, because research on the R form had proven the drug to be exquisitely safe. Later it was reintroduced, because of proven potency against leprosy and then other conditions, but it’s doubtful whether society will ever entertain the thought of utilizing thalidomide during pregnancy—even though there is no rationale for avoiding the pure R enantiomer. At least, convincing the public would require a major chemistry lesson.
Moving into the Future
The thalidomide story is a lesson on how enantiomers of a compound can have devastatingly different effects. Still, many drugs on the market work fine as racemic mixtures because the presence of both enantiomers does not contribute in any major way to undesirable effects. The NSAID ibuprofen is a case-in-point, as is omeprazole. The latter is used to treat gastric acid conditions, but when you pronounce S-omeprazole, it comes out ”esomeprazole,” the drug that AstraZeneca marketed under the trade name Nexium, with its own patent, based on the idea that the S without the R makes a difference. Indeed, there are some differences. For instance, there’s evidence that esomeprazole is more effective than omeprazole in settings of gastroesophageal reflux disease (GERD) symptoms. But esomeprazole and omeprazole both are proton pump inhibitors, so there has been controversy about whether AstraZeneca hyped the differences.
With the anesthetic ketamine, there is plain old ketamine, the racemic mixture, and what’s called S(+)-ketamine (esketamine). It is twice as potent as the racemic mixture, and it’s eliminated from the body much faster than the R enantiomer, R-ketamine (arketamine). Consequently, esketamine can be used as a lower dose to get the same effect, and a German study demonstrated reduced adverse effects, plus another benefit: especially potent neuroprotection. All of this together amounts to a qualitative difference in the effects of the S and R forms of the drug. And while it may not be as dramatic, or as tragic, as the case of thalidomide, such notable pharmacologic differences between enantiomers characterizes a sizable number of drugs, and so the new Scripps method should be quite welcome in the world of drug development.
David Warmflash, M.D., is an astrobiologist, science writer, and physician. He is principal investigator on a Planetary Society-sponsored investigation of the effects of the space environment on organisms.