As a chemistry student and lover of the subject, I have a student membership for the Royal Society of Chemistry, and with this comes a monthly subscription to their magazine CHEMISTRYWORLD. This gives me an in depth monthly catch up with what’s going on in the world of chemistry. In this month’s issue (July 2020) one article in particular caught my attention; “Treating our brains better” by Andy Extance.
The article starts with the worrying fact that big pharmaceutical companies are reducing their focus on developing new treatments for central nervous system (CNS) conditions despite there still being many conditions in need of treatments being found.
Why is this? Well it comes down to a few main factors:
- The struggle with getting the number of patients to complete clinical trials
- Drug approval processes may need to be altered for use with CNS drugs
- The brain is bloody complicated! (especially the issue with glutamate)
- Time (the more complicated the problem, the more time is required to figure it out)
In today’s post I’m going to discuss problems 3 and 4:
Problem no. 3: Glutamate
Glutamate is a neurotransmitter in the brain which has a main role in running the whole show, but too much is toxic, while too little and you don’t have a show (the brain can’t run as normal). So when developing treatments for motor neurone disease, obsessive compulsive disorder (OCD) and Alzheimer’s, in which there is a toxic amount of glutamate, the solution isn’t as easy as simply creating a drug that blocks this neurotransmitter. Instead a drug was developed which regulates it, kind of like those temperature control tights which stop your legs from getting goose bumps when it’s cold, but then also stop you dripping in sweat when it’s hot. The name of this drug is riluzole, and it ensures glutamate levels are kept healthy and steady.
But the problem is that it’s a very high maintenance drug which wants plenty of free space before it can be absorbed in the gut. This means it must be taken twice a day on an empty stomach1 and I’m not sure if there’s anyone who wants a drug dictating whether they can have a wee snack.
But as I’m always preaching on this blog, there’s hope!!
Enter stage left: prodrugs. Prodrugs are ‘ compounds which undergo a biotransformation prior to eliciting a pharmacological response‘ (I had this learnt off pat for my exams this year haha). Basically unlike the active drug, the prodrug is absorbed well in the gut, and so once it’s been absorbed, it undergoes some process to release the active drug which can then get to work. The best analogy that came to my mind when thinking of the mechanism of action of a prodrug, is like in TV shows in which children would be trying to get into an 18-rated movie by being on each other’s shoulder’s with a very long coat disguising it all so that they appear as one grown adult. Then once they’re past the ticket person they can undo their disguise and enjoy the film.
In the case of the most effective prodrug of riluzole, called troriluzole, once into the bloodstream it gets broken down by the action of enzymes (think of the children-stack being dismantled). Therefore, troriluzole only needs to be taken once a day and is not affected by how much you’ve eaten.1 So this prodrug is sounding very promising for conditions in which glutamate quantity plays a part, of which 10 conditions have been identified! A big pharmaceutical company, Biohaven Pharmaceuticals, is currently testing troriluzole in clinical trials for multiple conditions, including Alzheimer’s and OCD.
Check out Biohaven’s info on Glutamate’s Role in the Brain (I didn’t really keep up with all the scientific words in the video but it is a very good visual aid!!)
The issue with glutamate playing many parts in the show also highlights the need for new approaches to be used in drug discovery. In the past, drug discovery processes have focussed on one target protein, but substances such as glutamate interact with multiple different proteins, meaning that in order for effective treatments to be developed, attention is going to need to be paid to several different pathways.
Problem number 4: Time
Now for the issue of time. Due to the brain being rather complicated with a lot going on, it takes longer for drugs which act on the CNS (central nervous system) to be developed, than drugs which work on other parts of the body. And the more time you spend working on something, the more you really don’t want it to fail!
But a solution has been found for this too…
Teamwork makes the dream work!
Pharmaceutical companies, biotech companies and academics have joined forces with the benefit that more people and more expertise means faster results.
So it sounds like the scene of new drugs for treating the brain isn’t as bleak-looking after all, thanks to prodrugs and an ever-important bit of teamwork! 🙂
Hope you enjoyed this different kind of a blog post from me. I spent a lot of time wondering whether it was too far out of my niche but really there are so many different areas involved in mental health, and as the purpose of my blog is to promote and explore mental wellbeing there’s no reason why not too! (I also couldn’t resist amalgamating my two favourite subjects; mental health and chemistry)