Modeling neurotransmitter receptors

The third lecture and Chapter 5 of the course book handled synaptic transmission – especially chemical synapses, which play a huge role in developing effective psychoactive drugs, which could help e.g. in the treatment of depression and anxiety disorders. Chemical synapses work much more slowly than electric synapses, as it takes time for the release and diffusion of the neurotransmitter before the next neuron will be activated. The mechanisms of recycling the neurotransmitters are quite complex: in addition to simple diffusion, there are reuptake mechanisms which result in enzymatic degradation or recycling of the neurotransmitter. Alternatively, the transmitter can be degraded in the synaptic cleft. Autoreceptors at the presynaptic terminal often ensure that the signal transmission stops at some point.

As we have seen, the mechanisms and molecules related to synapses can be quite complex. It leaves you to wonder, how you could model the situation somewhat realistically. It must be essential to be able to, say, determine the proper dosage of psychoactive drugs. It should be understood, what the desirable levels of, for example, the monoamine neurotransmitters serotonin, dopamine or norepinephrine are. Excess and deficit amounts of these transmitters have been associated with many disorders, such as depression, ADHD and even schizophrenia [1].

One challenge is the discovery and analysis of the receptor structures involved in chemical synapses. Once it is known that by inhibiting a receptor we can have a certain effect on the brain, we have new questions. What kind of a molecule can we use to inhibit this receptor? What is the obtained level of inhibition? Modeling can offer some insight to this question. A pharmacophore is such a combination of features that defines how ligands are able to bind to a receptor. It may, for example, define locations of cationic and anionic groups and hydrophobic and hydrophilic parts of the molecule. The development of pharmacophore models and visual screening (VS) based on them can thus suggest molecules that would inhibit the receptor [2]. Drug development is often centered around the concept of trying to create compounds that have very similar structures to the ones that are known to work. Visual screening, however, can provide good potential inhibitors that have very different structures.

After this stage, however, many questions remain. How effective is that molecule in reality? Is it selective? Does it have potential side effects? Is it able to cross through the blood-brain-barrier? The deeper you go into this topic, the better you understand that we barely understand anything at all!

Posted by Meo Ekroos

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