Retrospectacle: A Neuroscience Blog

Are Your Drugs Right-Handed?

In recent years, pharmacutical companies have re-released several of their blockbuster drugs with a new twist. By carefully controlling the spatial arrangement of each atom in the active ingredient, chemists can increase the effectiveness of medications and sometimes prevent unwanted or horrible side effects.

Modafinil (provigil) is a treatment for narcolepsy. It also allows healthy people to stay awake for extended periods of time. Armodafinil (neuvigil) is a newer product that contains only one isomer of the drug.

Methylphenidate (ritalin) is a treatment for attention deficit hyperactivity disorder. More recently, Novartis has introduced dexmethylphenidate (focalin) which contains only a single isomer of the active molecule.

This is a bit heavy: Stereoisomers are molecules that have the same chemical formula and bonds, but a different arrangement of atoms. Enantiomers are a type of stereoisomer that are mirror images of each other — just like a right hand is the mirror image of a left hand. R-stereoisomers can be thought of as “right handed” and L-stereoisomers can be thought of as “left handed”.

In both cases, the generic names of the new drugs say something about their stereochemistry. Armodafinil sounds like R-modafinil, and in fact, it is the R-stereoisomer of the powerful stimulant. The prefix dex- in dexmethylphenidate indicates that when polarized light is shined through a solution of the substance, the polarization will rotate a bit in a clockwise direction.

Eszopiclone (Lunesta), Escitalopram (Lexapro), and Dexedrine are also pure enantiomers. Clearly, our brains are very picky about the shape of their drugs.

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  1. #1 Mick
    October 18, 2007

    Oh no…brings back nightmares of organic chemistry–although I do think stereisomerism is pretty cool. Another to add onto the list: Albuterol, where the R-enantiomer increases bronchial airway diameter, and the S-mirror image is a suspected inflammatory agent.

  2. #2 Aaron Rowe
    October 18, 2007

    Thanks, Mick! That is a fantastic example.

  3. #3 travc
    October 18, 2007

    Ah, brings back my undergrad days… (assuming what I learned was correct)

    Using Neproxen Sodium (Aleve) requires enantiomeric separation since one chirality is a very powerful anti-inflamatory, while the other is a potent liver toxin.

    I actually had a problem in a Chem Eng course to propose a separation process which could potentially be comericalized. It was one of those ‘we don’t actually expect you do be able to answer it’ sorts of questions, since if we could then we could make a butt-load of cash (Aleve was not yet on the market).

    Still not as bad as a question in a more advanced course, which was to design a synthesis process for Taxol (again before anyone had figured it out).

  4. #4 Pinko Punko
    October 18, 2007

    The reason this is a big deal for drug companies is they can get a new round of patent protection on the stereo-selective preparations. The most famous case of a drug having different effects for each stereoisomer is Thalidomide. One enantiomer treats morning sickness, the other causes birth defects. Because of how many drugs are made, you get a mix of both enantiomers in the synthesis.

  5. #5 lr
    October 18, 2007

    I certainly hope these drugs being re-released don’t racemize when they hit the body. As I recall, in vivo racemization was the problem with Thalidomide- they could make it in the pure (non-toxic) enantiomer, but, once in the body, it would interconvert to the toxic form. If there is any such effect from these drugs, producing the pure forms would be biologically useless- although a great source of revenue for the drug companies.

  6. #6 chezjake
    October 18, 2007

    Perhaps the most frequently used stereoisomer is dextromethorphan (the antitussive in most OTC cough medicines). It’s left-handed stereoisomer, levallorphan, is a potent narcotic analgesic.

  7. #7 Jenny Rae Rappaport
    October 18, 2007

    My o-chem background is extraordinarily rusty, but I can tell you another new drug that’s just one type of isomer too. Since Zyrtec is going generic in January, there’s now Xyzal from the same manufacturer… smaller pills (5 mg instead of 10 mg), less sedative effects, and studies that show that it’s better at treating chronic urticaria. I’m all for it. =)

  8. #8 Jeff Harrell
    October 18, 2007

    If I remember correctly, the R-enantiomer of albuterol that Mick mentioned is sold by Sepracor under the trade name Xopenex. At a significantly higher cost than racemic albuterol, I think.

  9. #9 Biomed Tim
    October 18, 2007

    “Clearly, our brains are very picky about the shape of their drugs.”

    I think receptors in general (all over our bodies) are just picky about the shapes of their ligands, no?

  10. #10 Kagehi
    October 18, 2007

    Read about this a number of years ago. Was creating a stir in some circles at the time, since there was several promising drugs that tested well in the lab, when taken from their direct organic source, but which somehow completely failed to work when made in the lab, then used on patients. Turned out, in that case, the handedness wasn’t just “reducing” the effectiveness of the drugs, but was actually counteracting the intended result. Sort of like if you tried to give someone an anti-inflammatory, only its mirror version was an inflammatory. Oops! Very interesting read. And, sadly, at the time there where a lot of researchers who didn’t believe that something like that could possibly have an effect on how a drug worked… Even highly intelligent people with degrees can be serious idiots some times. I don’t even have a degree in *any* kind of chemistry and it makes perfect sense to me. Maybe what they needed was more computer programmers to explain to them how “sort of similar interfaces” is not the same as “identical interfaces”. lol

  11. #11 z
    October 18, 2007

    ‘Turned out, in that case, the handedness wasn’t just “reducing” the effectiveness of the drugs, but was actually counteracting the intended result. Sort of like if you tried to give someone an anti-inflammatory, only its mirror version was an inflammatory.’

    Well, certainly, it’s predictable that somewhere along the line the enantiomer might be similar enough to be inhibitory; even something as simple as uptake in the intestines. Or, might be similar enough to bind to the target site, yet not activate it.

  12. #12 Drugmonkey
    October 19, 2007

    and let’s not forget ADHD med Adderall.
    from wikipedia we learn:
    “Specifically, Adderall XR is composed of the following proportions of active ingredients:

    * 1/4 dextroamphetamine saccharate
    * 1/4 dextroamphetamine sulfate
    * 1/4 aspartate (racemic d/l-amphetamine)
    * 1/4 sulfate (racemic d/l-amphetamine)

    These four salts are metabolized at different rates and possess diverse half lives, therefore resulting in a less dramatic onset and termination of therapeutic action; as compared to single salt amphetamine preparations.”

    a cynical person might venture that some of this onset/termination stuff could be managed by pill formulation and wonder just what effect size over good old d-amp HCl might actually be achieved.

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