She Blinded me with Science

Here is the cerebral post I promised. Warning: it's kinda long. So, you might want to go get a cup of coffee before you read this... and maybe something to draw a few pictures with (it might help.)

Friends, let's get chemical.

I have been able to explain this basic concept to two people in recent history, and they both found it interesting. I thought you might too. I realize that I am biased because it is chemistry. But, just hang with me. Even if you don't find it interesting, there is a point at the end.

Here we go... (where's my model kit?)

Carbon atoms have the ability to bond four times. Assuming that no double or triple bonds are formed, the other atoms bonded to a carbon are generally evenly spaced around the carbon, in all three dimensions. This forms a shape called a tetrahedron. (I don't have my chalk board, so you are going to have to envision it: it is not flat - picture carbon in the middle, with three atoms below it spread in a triangular shape, and the other atom is directly above the carbon.)

Now, let's say, for example that we bond a hydrogen (H,) a nitrogen (N,) a chlorine (Cl,) and a fluorine (F) to a single atom of carbon (C.) You could put the H, N, Cl, and F onto the C in any order you wish without it affecting the properties of the "molecule." (This would not be a stable molecule, but I use it for sake of simplicity.) So, if you went to the lab and mixed all of these things in a beaker, you would come up with a molecule with a formula something like CHNClF. And, if you added a new chemical to the beaker to react with this molecule, all the other molecules would react exactly the same way.

But that doesn't mean they are all the same. Imagine a specific molecule. If you were looking down (as described above, with carbon in the middle) let's say that these atoms were in the following positions: H at 2 o'clock, N at 6 o'clock, Cl at 10 o'clock. That would leave F in the spot directly above the carbon. Now imagine a second molecule that is identical. The two atoms are superimposeable. Neato. Two of the exact same thing.

Now, take ANY two of the bonded atoms, and switch their locations. This molecule can no longer be superimposed onto the original molecule. No matter how you turn it in space, it just can't happen. The two are now mirror images of one another. The carbon is called a chiral carbon, because it has these mirror images.

In fact, EVERY carbon is chiral if it has four DIFFERENT things bonded to it. And, in a lab situation, where you simply mix a bunch of stuff in a beaker to make a molecule such as this, you will always end up making a mixture of both molecules (the "original" and the "mirror." Such a mixture is referred to as racemic.) The reason you end up with a mixture, is because the bonding atoms will bump into different carbon atoms in different places. One H bumps (and bonds) into a C at the 2 o'clock position, but another H might bump a different C at 6 o'clock.

The mirror-image molecules are called enantiomers. Chemists call one molecule "R" and the other "L." * (Like our Right and Left hand, which are also mirror images.) There are criteria for determining which is which, but it isn't important here.

But, this whole R and L thing is not such a "big" deal, since, as mentioned above, both molecules behave exactly the same way, chemically.

UNLESS...

The molecule happens to be a drug in your body. (So as to minimize any panic, what I am about to say is not true of every drug. But it is true of drugs that can be categorized as I describe below.) And that's where this all gets interesting. (Hopefully.)

Now, think back to your high school biology book. They all have a picture somewhere of an antibody or something, binding to a cell. The cell was always illustrated as a "blob" with a "key-shaped" hole. And the antibody was always illustrated as another blob with a key-shaped protrusion. The idea being that this specific antibody could only bind on cells with key-shaped holes. The concept is the same here. Keep this in mind, and I'll get back to it.

Almost all drugs are molecules that are made of a lot of carbon chains, linked into strings or rings, and frequently with branches. And there are tons of things that can be bonded to these carbons. Remember ONLY a carbon that has four DIFFERENT things bonded to it is chiral. But the four things are not limited to single atoms... it could be another branch or ring or something like that. So you might have a H at 2 o'clock, a ring structure at 6 o'clock, a branch at 10 o'clock and another C directly above. (And the mirror image of that as well.)

Anyhoo. Having a chiral carbon in a drug isn't even such a big deal....

UNLESS....

That chiral carbon holds the "key" that attaches to the cell in your body. Remember the receptor on a cell has a very specific shape. If the receptor has a hole that receives H at two o'clock, ring at 6 o'clock, branch at 10 o'clock, and C above, then only that specific enantiomer will work on the cell.

Ibuprofen is just like that. The part of the molecule that relieves the pain involves a chiral carbon. When you swallow an ibuprofen pill, you swallow both the R and L enantiomers. But only one is actually doing the trick. The other one is just floating around your body doing nothing.

We hope, anyway. Because.....

If there are unknown receptors on cells that just happen to be shaped like the other enantiomer, guess what is going to happen? The other enantiomer will start doing something... though what that is, no one knows.

This was the problem with thalidomide. It was used in the UK in the 50's and 60's as a tranquilzer for pregnant women. While one enantiomer worked to tranquilize the mom, the other enantiomer was busy giving their babies birth defects. (A fun example, I think, of how we can't always refer to chemicals as "good" or "bad" since these were, in fact the *same* chemical.... but now I am off on a tangent.)

So, as of 1995, the FDA has required that all new drugs be enantiomerically pure. In other words, you can only put the enantiomer that "works" into a pill before you market it.

Why did I just waste my time telling you all this? First, because it is interesting... whether you like it or not ;) Second, because, IMHO, I think this can drastically effect the cost of drugs.

Remember, enantiomers have the same chemical and physical properties. Drug companies can no longer make drugs in a way that lets atoms bond wherever they want. If they do, they end up with a racemic product... and how the heck to you separate the R molecules from the L's if they will all react the same way? It can be done, but it requires additional processes, on top of the initial manufacturing. However, I am guessing this is not the preferred option, b/c then they'd be left with a whole lot of the other, useless, enantiomer.

The other option is to figure out how to produce these drugs so that only one specific part of the molecule can bond at a time, and figure out how to get that part to bond in a very specific place on the carbon. (Reason #692 that I did not become an organic chemist.) This tends to increase the number of steps and the number of chemicals used in the manufacturing process. And that ain't cheap.

I tell you all of this simply because I don' think most people know, yet it is an easy concept to grasp (assuming I have taught you well, I suppose!) And, I think it sheds some light on a topic of concern for some (many?) people.

And, not to put the FDA on a pedestal, or anything (we all know they haven't exactly go it all together over there,) but, until I know more about how this kind of thing is handled around the world, it makes me reluctant to jump on the "buying-drugs-from-other-countries" bandwagon.

Thanks for playing. Hope you found it interesting.

Thanks to Nelson Sartoris for supplying the info about thalidomide.

*CORRECTION - enantiomers are labelled R or S, not L, as originally posted. My bad!

For an interesting article related to this (which is not completely impossible to comprehend) click here. It offers some interesting information some of which sheds new light on my understanding and presentation of this topic. (12/15/05)