DAVID MANALLACK: Hi. In this chemistry module, we will take a look at the evolution of drugs used for treating depression. From simple chemical starting points, medicinal chemists have been able to liaise with clinicians to understand how their drugs worked. The modifications made to these compounds have sometimes dramatically altered their biological actions and clinical profiles. From Maria’s perspective, our understanding of the chemistry of depression gives us insight into helping her with her condition.
The origins of antidepressants can be traced back to the 1930s, when the first antihistamines were being developed by a French company, Rhone-Poulenc, to treat allergies. If we build up the structure of one of these compounds, phenbenzamine, we start with a benzene ring. And adjacent to this ring is another benzene ring. The two rings are joined by a short, two atom chain, where one of these atoms is a nitrogen. Attached to this is another short chain that ends with a basic amino group with two methyl groups attached. The theme of two aromatic rings and a basic nitrogen is carried through in this module as we evolve this compound into modern day, antidepressant medications.
From these early origins of antihistamines, there emerged a wide range of compounds. Shown here is the anti-psychotic compound, chlopromazine, which was discovered to great effect in the 1950s. Once again, we see the presence of two aromatic rings now bonded together by a sulphur atom. And there’s a short chain to the basic amino group.
A simple chemical modification to the three ring system of chlorpromazine gave us the first tricyclic antidepressant drugs, which included imipramine.
This period of the 20th century was a rich phase of drug development, with projects leading off in several directions to discover new antihistamines, anti-psychotics, and antidepressant drugs. While numerous classes of drugs emerged from this early work, they often had side effects because they were not specific enough. Treatment with tricyclic antidepressants resulted in sedation and constipation, along with many other side effects. Clearly, better drugs were needed. Key to the development of improved drugs was establishing just how the tricyclic antidepressants were able to treat this condition. In the 1960s, it was found that the tricyclic antidepressants inhibited the reuptake of noradrenaline and serotonin. So let’s have a look at the chemical structures of these natural neurotransmitters.
First, we will examine noradrenaline. The molecule comprises a benzene ring with two hydroxyl groups. Attached to this is a two carbon chain with a hydroxyl group and a basic amino group. Serotonin has some similarities to noradrenaline. It too has an aromatic system that comprises two rings with a hydroxyl group. There’s also a two carbon chain to a basic amino group. As we’ve heard from a biology perspective, when serotonin is released during neurotransmission, some of the compound is actively taken back into the cell in a process known as reuptake.
Now interestingly, at the time when tricyclic antidepressants were discovered to inhibit noradrenaline and serotonin reuptake, simultaneous research found that certain antihistamines, including diphenhydramine, could also block serotonin and noradrenaline reuptake. This animation compares the tricyclic antidepressant imipramine with the antihistamine diphenhydramine. Looking at both compounds, it is clear that there are some structural similarities between them. Both compounds have two aromatic benzene rings attached to a short carbon chain that leads to a basic nitrogen atom. Superimposing these compounds highlights their structural similarities.
The common chemical scaffold is shown here in red. From this molecular comparison, we can speculate that it is possible that both molecules interfere with the reuptake of noradrenaline and serotonin in the same way. Brian Malloy and Klaus Schmiegel, working at Eli Lilly in the USA, used diphenhydramine as a starting point to develop reuptake blockers. The subtle modifications of changing the linkage between the two rings by moving the oxygen atom produced nisoxetine. As a research tool, nisoxetine was very useful as it was more selective at inhibiting noradrenaline reuptake with lesser effect on serotonin reuptake. Nisoxetine, however, was never marketed as a human medicine. From nisoxetine, a further small change led to fluoxetine.
The CF3 group, or trifluoromethyl group, was the key to giving this molecule the ability to selectively inhibit serotonin reuptake. And this compound was marketed in 1987 as Prozac. As this compound is very specific for serotonin reuptake, it has fewer side effects than the tricyclic antidepressants. Prozac also gave us the name for this class of drugs, which are termed Selective Serotonin Reuptake Inhibitors, or the acronym SSRIs.
For some of the chemistry modules we’ve discussed in this course, we’ve had information about the interactions these drugs make with their target proteins.
In this particular case, we have information on a related protein that binds the SSRIs and tricyclic antidepressants. This protein gives us tantalising clues to how these compounds work and may, in the future, help us to design better drugs to achieve better health outcomes. So at this point, we’ve developed an article to read to take you through to the new medicines in this area.