Chirality, a Primer (Updated)

    The word chirality comes from the Greek word for "handedness," as in left or right-handed.  Well it turns out molecules can also have different forms that are analogous to the idea of handedness.  For an example look at alanine.  The figure shows two versions, or what chemists call enantiomers, of the amino acid alanine.  Much like each hand has five fingers, one thumb, ect both molecules have the same number of atoms and same general chemical structure, but make no mistake these are two distinct compounds.  

     Chemists have different ways of naming the different enantiomers.  There are three different systems for naming, the S/R system is preferred by chemists and involves numbering the atoms bonded to the center of the plane of symmetry (the chiral carbon).  The +/- system is based on how each enantiomer shifts light, either in a (+) dextrorotary (clockwise), or (-) levorotary (counterclockwise) direction.  Finally there is the D/L system of naming, which has nothing to do with light and is based on the labeling of the biological molecule glyceraldehyde.  Confused yet?  Me too.  All you really need to know is that these are two distinct molecules.  

     Chirality is an important chemical concept, particularly for pharmacology and medicinal chemistry.  Most drugs work by interacting with a specific receptor, oftentimes described like a key (drug molecule) fitting into a lock (receptor).  It is not uncommon for receptors to respond to only one of the two forms, if the receptor was a left-handed glove it would fit well with a left hand but not very well with a right hand.  One of the most famous examples of different pharmacological effects due to chirality is methamphetamine.  

     Methamphetamine has two enantiomers, L-meth and D-meth.  D-methamphetamine is the good stuff, well I personally wouldn't touch the stuff as coffee gets me as stimulated as I care to be, but D-meth is what speed aficionados like.  L-meth is much weaker with little effect on the central nervous system, although it is a good decongestant and is even used in Vicks inhalers!  

    When drugs are synthesized in a laboratory, the chemical reactions often result in a 50:50 mix of the enantiomers, called a racemic mixture.  Because the two drugs have the same basic chemical structure, they are share physical properties (solubility, melting point, ect), which makes them difficult to separate.  In some cases, such as virtually all the methadone sold in the US, what people are actually getting is two different drugs with different pharmacological properties.  

     Methadone such as is dispensed at clinics across the US, is a 50:50 mix of (S)-Methadone and (R)-Methadone.  The only difference is the direction the methyl (CH3) group is facing, in the diagram to the left, in (S)-methadone the methyl is pointing forward as signified by the solid black line.  In (R)-methadone the methyl is facing away from the viewer, into the page as signified by the dashed line.  For another view of the two enantiomers see the three-dimensional methadone models in the image.  The white arrow points to the methyl group, otherwise the molecules are identical.   

   The position of that methyl has a large effect on methadone's opioid properties.  For all practical purposes, only (R)-methadone actually has any opioid effect.  One possible explanation for this has to do with the space between the nitrogen (blue in model) and the oxygen (red).  In (R)-methadone the methyl is facing away from the space between the oxygen and nitrogen, which allows a bond to form.  In (S)-methadone the methyl group is blocking this space.  

It should also be noted that not all molecules have mirror images, hence they are achiral.  Other molecules have more than one chiral center, and the number of different combinations of enantiomers (called stereoisomers) grows exponentially.  For example morphine has five chiral carbons, marked with red dots.  Theoretically at least, morphine has 32 different stereoisomers.  Fortunately plants (and animals) are masters of biochemistry and are able to produce a single specific form of morphine, as all the different stereoisomers could have different pharmacological effects.  This is also a reason why poppies are still used as the source material for all opiates currently used in medicine today.  

Update, 12/3/2012

     If you are taking methadone what does this mean for you.?  If you live in the US, and probably most of the world (there may be places where you can get enantiomerically pure (R)-methadone, I just am not aware of any) you are getting a racemic (50:50) mixture of R/S Methadone.  (R)-methadone is 10-50 times stronger than (S)-methadone, so for all practical purposes only half of your dose is actually an opioid.
    This becomes relevant clinically because the different enantiomers have different pharmacological properties.  Take peak-and-trough testing for example.  Let's say you are on a high dose of methadone but wake up every morning feeling sick.  You request an increase but since you are already on a high dose the clinic says, "Hold up there we can't take your word for it, you're a junkie and everyone knows junkies lie so we are going to confirm your feelings with a blood test."
    Peak and trough testing is a blood test that measures the level of methadone at two points in a 24 hour period.  The first is right before dosing when the methadone is lowest (the trough), then another blood test occurs about 3 hours after dosing when the methadone has reached maximum blood concentration (the peak).  Supposedly based on this test they can tell if you really need additional methadone.
     But here's the thing, the blood test does not distinguish between (S)- or (R)-methadone.  While they are similar in structure and share many pharmacological properties, they are not the same.  An individual may metabolize (R)-methadone faster than (S)-methadone, so that by the time they wake up in the morning the level of (R)-methadone is way down and they are beginning to feel withdrawal.  However their blood is still loaded with (S)-methadone, so the peak and trough test, which does not distinguish between R and S enantiomers, gives results that indicate the level of methadone is adequate.  And so the doctor with their test results can tell the patient it's all in their head, when in reality there is a clinical reason why the person wakes up every morning feeling ill.  The patient should always be trusted when it comes to their own body.
     There may be other differences in the two enantiomers.  Methadone has action on other receptors besides the endorphin receptors.  Would there be any advantages to using pure (R)-methadone?  At this point I am not sure but will revisit this issue as I learn more.

Read more about Peak and Trough testing here.