Smoking chemistry: part 1

DAVID MANALLACK: Hi. Nicotine is a substance that’s very familiar to most people. Its introduction to Europe in the 16th century saw it being used for smoking and later as an insecticide. Nicotine itself is extremely addictive, as Tracy has found out. Medicinally, it has very limited use. And yet, it is sold in pharmacies worldwide. The reason? Well, it’s used for helping with smoking cessation. Quite simply, replacing the nicotine in cigarettes with nicotine gum or patches allows users to limit or cease smoking cigarettes altogether. Our chemistry story in this module will look at the structure of nicotine, and to examine the important features of this molecule needed for binding to its receptor. Nicotine comprises two rings.

The first ring is aromatic in nature and differs to benzene by replacing a carbon atom with a nitrogen atom. And this is known as a pyridine ring. The second ring is made up of five atoms, one of which is a nitrogen atom that has a methyl group attached. This ring is known as a pyrrolidine ring. Joined together, we get nicotine, so named after the Latin name of the plant it is derived from, Nicotiana tabacum.

Let’s have a look at its chemical structure more closely. The five-membered ring of nicotine has a nitrogen atom that is basic in nature. This means that in the bloodstream, it bears an extra hydrogen atom and has a charge of plus 1. The second notable feature of nicotine is the bond between the two rings. You’ll notice that this bond is drawn as a solid wedge. This provides us with some three dimensional information about nicotine. It indicates that the six-membered Pyridine ring is oriented towards the viewer. In reality, nicotine can exist in two forms. Each form is a mirror image of the other molecule. In two dimensions, we would show these structures with a wedge and a hashed bond.

The hash tells me the ring now points away from the viewer.

Interestingly, the molecule on the left is biologically active while that on the right is inactive. And for the world of drugs and medicines, this is very important. A lot of our drugs come in these mirror image forms, and we strive to only give the active form. Morphine is a good example where only one mirror image form gives you pain relief. We can think of this as we would our hands. Our hands are mirror images of each other such that we can’t superimpose them. This aspect of chemistry is called handedness, or chirality. Let me explain this for nicotine using an animation. To begin with, this animation shows nicotine with the six-membered pyridine ring coming out towards the viewer.

I will now introduce the inactive version of nicotine on the right.

As we rotate this round, we can see the mirror plane.

Finally, we have the active drug on the left and the inactive drugs on the right. As one drug is inactive, this tells me that the binding site for nicotine in the receptor must have the complimentary shape of the active drug. The receptor only will bind the active form of nicotine. The last aspect of nicotine we want to discuss is the flexibility of this compound. If we look at this in simple terms, the two things are free to rotate relative to each other. And this gives us a dilemma. Given that it is flexible, we are not sure which conformation– and by that, I mean which orientation of the two rings– is relevant when nicotine binds to the nicotinic receptor.

In medicinal chemistry, we are often asked to design new molecules. And knowing which conformation is the biologically relevant one can be extremely useful.