Molecule of the Day

L-methamphetamine is a fine example of how molecules that vary only in their chirality can have very different biological effects. Chiral molecules have non-superimposable mirror images. L-methamphetamine, at left, below, is found in Vicks Vapor Inhalers. (Notice how they obfuscate the name a little bit by calling it “levmetamfetamine”). This is the mirror image of D-methamphetamine – the street drug. As you’ll see, the two compounds are very different medically despite having only a subtle structural difference.

i-4f7ea4a18b30b0c2bbd2f9b08190dfd6-vicks.JPG

i-ca4d200778f47459f142ec6aff31aa70-methamphetamine.gif

If you’re having trouble working out the difference, the dashed bond is “going into the plane of the page (monitor).” That is, in 3-D, it’s around the back side of the molecule. If you’re having trouble figuring out the significance of this, you’re not alone. A good chunk of chemists only get the hang of this after playing with “molecular models” – pretty much chemistry tinkertoy. Just think of the two molecules as left and right feet and you’re on the right track.

The thing is, L-methamphetamine isn’t really anything like the D-methamphetamine isomer that is found in street drugs. D-methamphetamine is psychoactive, while L-methamphetamine isn’t very psychoactive at all. In certain receptor and enzyme pockets where D-methamphetamine fits, L-methamphetamine fits like a left foot in a right shoe.

Because of this, the L-isomer only induces some of the same effects as the illicit D-isomer (like increased blood pressure, which is responsible for its efficacy against nasal congestion), while not effectively inducing others (such as the euphoria and stimulant effects).

This is the only case I know of where the opposite stereoisomer of an illegal drug is actually over the counter!

For some more talk about chiral drugs, take a look at Derek Lowe’s blog.

That’s the end of weird drug week. See you Monday.

Comments

  1. #1 chezjake
    October 27, 2006

    Another good example of this paradox in activity is the difference in pharmacological activity between dextromethorphan (used in many over-the-counter cough syrups) and levomethorphan (a potent, narcotic analgesic). Interestingly, in this case it’s the levo-rotatory stereoisomer that is the more dangerous of the two.

  2. #2 Jean-Claude Bradley
    October 28, 2006

    Another example is dextromethorphan, used as an over the counter cough medicine. The other enantiomer is a potent opioid analgesic.

  3. #3 H.F. Burns
    October 28, 2006

    “This is the only case I know of where the opposite stereoisomer of an illegal drug is actually over the counter!”

    Dextromethorphan, a cough suppressant that is the D form of an active opiate, is another.

  4. #4 MoTD
    October 28, 2006

    Thanks to all three of you for pointing it out :) This actually didn’t miss my attention, I was about to put it in, but I couldn’t find much about L-methorphan use, commercial or street (other than some laws banning this enantiomer specifically). Levorphanol, however, which is levomethorphan with a phenol instead of a anisole functionality, is sold commercially.

    Good catch though, I was wondering if someone would hop on that sentence. Let me know if you know more about L-methorphan, I’ve only ever heard it mentioned in the same breath as D-methorphan. Does anyone actually take L-methorphan?

  5. #5 Adam
    October 28, 2006

    Another chiral drug with an interesting (and well-known and tragic) history is thalidomide. One enantiomer is effective against morning sickness, whereas the other causes birth defects. The stuff they used was racemic, but even giving just the one enantiomer wouldn’t have helped, as they’re converted from one to the other in vivo.

  6. #6 Joe
    October 29, 2006

    If I may suggest …

    When you want novices to see the difference between enantiomers, it is better to draw them in the same orientation. Doing that shows the relationship between them more readily, and the wedge vs. dash bond stands out.

  7. #7 Derek Lowe
    October 29, 2006

    Thalidomide is the classic chirality example, but the story turns out to be more complicated than most people think. . .

  8. #8 Charlie
    October 30, 2006

    “Methamphetamine” was detected in Alain Baxter’s post-race urine sample after his superb third place in the Men’s Slalom at the 2002 Salt Lake City Winter Olympics.

    Despite the sample being identified as “Lev-Methamphetamine” and having it’s source identified as a Vicks Nasal Inhaler, and with the court of arbitration acknowledging there was a valid reason for it’s presence, and absolutely no performance advantage, Baxter was still stripped of his bronze medal.

    It remains, to this day, one of the greatest miscarriages of sports-justice.

  9. #9 Nairn
    October 30, 2006

    Clearly, none of you boffins have abused Dextromethorphan (commonly known simply as ‘DXM’) for your own psychoactive amusement. Whilst I’m sure (or rather, hope) it’ll never make a common-place street drug, it is one of the most surprisingly potent drugs I have ever consumed, offering [me] a distinctly profound, internalised mental ‘trip’ or experience.

    Interesting article, thanks!

  10. #10 Paul Begley
    October 30, 2006

    First, thanks for a Molecule of the Day post, I will pass this on to my daughters (who will frown, whine, but probably be interested nonetheless).

    Second, The L and D prefix can also be referred to as levorotary (left-handed) and dexorotary (right-handed).

    I believe sugar is another example of a molecule which forms left and right handed crystals. As I recall, Ben Franklin noted this and later research determined that one form is metabolized by the body, the other is not.

    I don’t have any references handy to confirm this.

    -Paul

  11. #11 Joe
    October 30, 2006

    Paul B,

    You are a tad confused. lower-case l and d are used to designate the sense of light rotation. Big D and L refer to an old system of identifying isomers, and is independent of light rotation.

    I am not entirely clear on the history of optical isomers; but Louis Pasteur is famous for noting and separating crystals of enantiomers.

  12. #12 Thomas
    October 31, 2006

    Another example of an illegal/popular OTC pair of enantiomers(at least in the US) is ephedrine and pseudoephedrine.

    It’s not as good an example as there are two chiral centers in the molecule so you don’t get a perfect mirror image, and since ephedrine is less illegal than meth.

  13. #13 allan
    September 25, 2007

    can that shit make you high

  14. #14 Simon Samaha
    October 23, 2007

    A question: are the small letter designations identical
    (chemichally) to the corresponding capital letter ones ?

    For example, is l-methamphetamine identical to
    L-methamphetamine ?
    and is d-methorphan the same as D-methorphan ?

  15. #15 Simon Samaha
    October 23, 2007

    2nd message; another question.

    How can I get or get to make a station and be involved in this kind of blogging ?

    I have background in college chemistry including organic,
    but am myself a mathematician. I can and would like to give and hopefully recieve. It would be great of you if
    you have direction. Thanks and take care.

  16. #16 Peter Spencer
    December 13, 2007

    The uncommon amino acid beta-oxalylamino-L-alanine (L-BOAA) is a potent glutamate AMPA agonist and neurotoxin present in the free form in Lathyrus sativus (Grass Pea), an environmentally tolerant legume used as a subsistence and famine food in the Horn of Africa, the Indian sub-continent and, formerly, central Spain and north-central China (Gansu Province). A crippling motorsystem disease, lathyrism, has occurred in all these sites at some point during the past 70 years. While L-BOAA is glutamate-mimicking neurotoxic substance, its stereoisomer D-BOAA lacks the AMPA-displacing and excitotoxic properties.

  17. #17 Jody
    May 3, 2010

    Actually, dextromethorphan, the antitussive (cough suppressant) fits in the same boat. It’s leverorotary form, levomethorphan, is an opiod. It must be demethylated by liver enzymes before it’s active. But, once active, it’s close to the same potency as morphine. Weird, huh?

  18. #18 juanita
    June 1, 2011

    The article author and many of the commentors above have shown a lack of knowledge about the use of D/L vs d/l in chemical nomenclature.

    For your future knowledge D/L is only used in sugar nomenclature and the molecules above are not part of this group. It compares the orientation of molecules vs the first sugar whose structure was found. It is really a biochemistry notation and its use is discouraged by the International Union of Pure and Applied Chemists.

    The correct nomenclature is d/l which refers to the way that the pure isomer (form) rotates polarised light. Anyway enough of that chemistry lesson.

    For those of you who are interested in Australia Vicks inhalor does not contain l-methamphamine. In fact, the law in my state (QLD) does not distinguish between the two as it states that methamphetamine, its isomers and derivatives are all illegal.

  19. #19 Josh
    March 6, 2012

    An Answer (to Simon’s question): the direction which an optically active molecule twists plane polarized light is not a function of its (R) or (S) conformation. The two are mutually exclusive. Having said that… the S conformation of methamphetamine produces dextrorotation of plane polarized light. I hope you are now delightfully confused! Happy trails! BZZZZZZZZ

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