Depression and its treatment with various antidepressant medications is very much a “hit or miss” process. A medication that works for one individual may not work for other patients, a process made even more unbearable by the 2-4 week latency period that most antidepressant medications require before their effects (or lack thereof) become apparent. One key piece of missing information for scientists has been how, precisely, so-called “tricyclic” antidepressants (named for their chemical structure) interact with the body.
Medication for depression is believed to work by preventing brain cells (neurons) from “soaking up”, or uptaking, the chemicals that neurons use to communicate. If neuron A wants to send a signal across a short gap (synapse) to neuron B, it does so by releasing chemicals known as neurotransmitters. These molecules, such as serotonin, norepinephrine, and dopamine, then float across the watery synapse and are recognized by neuron B; the signal is then complete. For some reason, patients suffering from depression have lower levels of these neurotransmitter molecules in their body.
Depression medications therefore are mainly in the “SSRI” class (selective serotonin reuptake inhibitor). They prevent neuron A from reabsorbing the neurotransmitters that it just released, making sure that there is the maximum amount of molecules available to float across the synapse and make it to neuron B. However, up until now it hasn’t been precisely clear how these medications function. This lack of understanding is part of the reason that multiple drugs are usually tried for a given patient before finding one that works, and the common side-effects from antidepressants (weight gain, loss of libido) are also a result of incomplete scientific understanding of molecular action. Chemists can’t maximize the efficiency of a medication if they don’t understand what part of the molecule needs to be changed – how the molecule needs to be altered, in order to increase the beneficial interaction with the body.
This crucial information has now been gained. Researchers report in the journal Science that they have mixed various tricyclic antidepressants with a protein called the leucine transporter protein. This molecule is very similar to neurotransmitter transporters in humans, the molecules which mysteriously interact with antidepressants and become “blocked” so that serotonin remains in the synapse and can more efficiently do its work. After mixing the molecules together, the researchers were able to crystallize the complex of the medication and the protein together – a very difficult feat; proteins are notoriously hard to crystallize in sufficient purity for analysis.
This crystal (consisting of the TCA medication bound to the protein) was then analyzed using X-rays, which is a technique whereby X-rays are bounced through the crystal lattice of the sample and the resulting scatter diagram is deconvulted via computer analysis to gain a computer three-dimensional image of the molecule. The chemists were finally able to see with their eyes how, precisely, the medication and the protein were interacting. It turns out that the drugs were locking into a particular cavity which is right next to the point where serotonin and the other neurotransmitters would be reabsorbed. By binding to this cavity, the antidepressants make a slight change to the structure of the protein, which prevents the adjacent cavity from soaking up the neurotransmitters. Now that scientists have a detailed image of how the medication works, they can design new molecules which bind more strongly, which will lead to stronger antidepressants which require lower dosages and therefore have less side effects.
Depression is a terrible disease, but it is not one which is being ignored by chemists and researchers. Now that synthetic organic chemists have a molecular diagram – blueprints, of a sort – of the way that the current antidepressants work, the researchers can go into the lab and design a whole new generation of medications.
“LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake”.
Zheng Zhou, Juan Zhen, Nathan K. Karpowich, Regina M. Goetz, Christopher J. Law, Maarten E. A. Reith, Da-Neng Wang.
Science magazine, published by the American Association for the Advancement of Science.