Medical science still doesn’t completely understand how the brain works. The strategy for treating brain disorders such as anxiety and depression seems to be therapy combined with medication. However, there hasn’t been a really straightforward method for developing new antidepressants. As a synthetic organic chemist of 12 years experience (post graduate), I can see the problem clearly. The antidepressants in use today don’t share a common molecular fragment. If you look at the structure of two of the most common antidepressants – Prozac and Lexapro – you see that both molecules have similar chemical elements (atoms of fluorine, nitrogen, oxygen, carbon, and hydrogen). However, the same can be said for millions of organic compounds. You have to look deeper than the elemental composition.
Organic chemists rely on something called “structure:property relationships” to predict how a compound will react in a given setting. The logic is that compounds which are very similar in structure will (most likely) have very similar properties. Conversely, compounds with very similar properties often have very similar structures. Take the structures of penicillin and amoxicillin, for example; these are two of the most popular antibiotics. Both of them have virtually identical chemical structures. Amoxicillin has an extra ring system, but the important four membered ring is present in both.
Antidepressants don’t have a similar logic in their molecular design. There is no common carbon skeleton shared by most antidepressants. This means that when someone doesn’t respond to a certain medication (as is often the case with psychiatric medication, in my experience), a vastly different molecule has to be tried. For an organic chemist, the lack of this common logical system means that it is extremely difficult (if not impossible) to predict if a new compound is going to have antianxiety or antidepressant properties. It has to be tested. When you consider that there are hundreds of thousands of new organic compounds prepared each year, the enormity of the task becomes clear. What is needed is a simple “screening” test that can be done rapidly in the lab, without the need for test animals, and which would point out whether a given molecule is promising for depression medication. Otherwise, organic chemists such as myself don’t know which direction to take in the laboratory.
That’s why I was very excited to read a recent article in the Journal of Clinical Investigation that describes a new screening method for small, non-polymeric molecules. There is recent research indicating that depression may be caused by faulty brain communication; this is caused (in part) by a protein called Brain Derived Neurotrophic Factor, or BDNF. This molecule is needed in the brain for normal brain signaling, but it has a receptor that can contribute to anxiety and depression. By blocking that receptor with a drug, the depression would (in theory) be cured. The researchers in this article used a technique called “KIRA-ELISA concentration-response assaying” to rapidly sort through hundreds of potential drug candidates, finally settling on the one or two molecules which were found to reduce cellular processes associated to the BDNF receptor for depression (called TrkB). In mice testing, the chosen drugs were found to reduce anxious behavior in the rodents.
This type of rapid molecular screening is exciting to chemists everywhere. We have an “embarrassment of riches” when it comes to potential new psychiatric drugs – there’s simply too many candidates. By using KIRA-ELISA to rapidly sort through the haystack, eventually one or two precious slivers can be found which will hopefully lead organic chemists such as myself in new and promising directions. Eventually, new antidepressants will be developed which will help the millions of Americans diagnosed with this disease.
The source of this article can be found at:
Cazorla, M.; Premont, J.; Mann, A.; Girard, N.; Kellendonk, C.; Rognan, D. “Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice”. Journal of Clinical Investigation, 2011, 121, 1846-1857.