Discovery of Selective Ligands for the Modulation of NMDA Receptors
(2025) KEMR45 20242Department of Chemistry
- Abstract
- NMDA receptors are part of the family iGluRs that regulate the flow of positive ions, such as Na+, K+ and Ca2+, by ligand gating. Upon activation with Glutamate, the channel opens, and a flowthrough of ions occurs. NMDA receptors are unique in that they require the co-agonist glycine for activation and that they exhibit voltage-dependent ion flow due to Mg2+ blockade. The NMDA receptors have three subtypes, GluN1, GluN2 and GluN3 which in turn have subunits of their own. The NMDA receptors are constructed with two GluN1 subunits together with two GluN2 and/or GluN3 subunits. The GluN1/2 receptors are more important from a physiological perspective; thus, these receptors are the focus of this thesis, specifically GluN1/2A and GluN1/2B.
... (More) - NMDA receptors are part of the family iGluRs that regulate the flow of positive ions, such as Na+, K+ and Ca2+, by ligand gating. Upon activation with Glutamate, the channel opens, and a flowthrough of ions occurs. NMDA receptors are unique in that they require the co-agonist glycine for activation and that they exhibit voltage-dependent ion flow due to Mg2+ blockade. The NMDA receptors have three subtypes, GluN1, GluN2 and GluN3 which in turn have subunits of their own. The NMDA receptors are constructed with two GluN1 subunits together with two GluN2 and/or GluN3 subunits. The GluN1/2 receptors are more important from a physiological perspective; thus, these receptors are the focus of this thesis, specifically GluN1/2A and GluN1/2B.
The NMDA receptors are known for their role in excitotoxicity, which make them important targets for potential drugs against e.g. Parkinson’s disease and Huntignson’s disease. It has been proven difficult in making potent drugs for the NMDA receptors due to the high risk of side effects. The reason for this is that the different subtypes of the NMDA receptors are similar in structure but also that they are widely spread across the brain, thus targeting only one receptor is challenging.
TCN213 is a scaffold that is selective for the GluN1/2A receptor with sufficient potency, binding at the interface, and able to cross the blood brain barrier. However, research on improving its potency and metabolism is ongoing. Different amide bioisostere analogues of the TCN213 scaffold have been synthesized to explore the amide part of this scaffold and study its importance in TCN213s activity. Important information of non-conserved amino acids between the subtypes GluN1/2A and GluN1/2B, specifically a switch from valine 267 to phenylalanine 262 respectively, have highlighted the theory behind the synthesis of the GluN1/2B analogues. Different synthetic approaches have been used to synthesize potential NAMs for the GluN1/2A and GluN1/2B receptors. However, their activity is yet to be determined. (Less) - Popular Abstract
- How can a drug enter the body and magically fulfill its intended purpose? To be able to understand this, one must understand what the drug is targeting in the body. The target in this thesis is a specific receptor. Receptors can be located in the brain and can be associated as a communicator. They receive information and distribute it to the rest of the body. However, the question of how remains.
Think of it in three steps. Firstly, the drug must be able to reach the intended receptor. Secondly, the drug needs to do this without being decomposed on the way and lastly, it needs to fit inside the binding pocket of the receptor and activate or deactivate it. All these steps are used in theory, when synthesizing a potential drug. These... (More) - How can a drug enter the body and magically fulfill its intended purpose? To be able to understand this, one must understand what the drug is targeting in the body. The target in this thesis is a specific receptor. Receptors can be located in the brain and can be associated as a communicator. They receive information and distribute it to the rest of the body. However, the question of how remains.
Think of it in three steps. Firstly, the drug must be able to reach the intended receptor. Secondly, the drug needs to do this without being decomposed on the way and lastly, it needs to fit inside the binding pocket of the receptor and activate or deactivate it. All these steps are used in theory, when synthesizing a potential drug. These different pieces are all needed to finish the puzzle. If one piece is missing, the puzzle can’t be completed.
The first puzzle piece can be described as going out to find chanterelles in the forest. It is raining and it is dark, therefore one needs an umbrella and a flashlight to be able to go outside in the first place. After reaching the forest, one walks and walks not knowing exactly where to go but eventually, after covering enough ground, a trail of chanterelles leads you to the right spot. The same is for the drug. It enters the body and is designed in a way for it to be able to reach its intended receptor. It then makes its way around the bloodstream until it finally finds that one receptor that it fits into.
The second puzzle piece can be described as a game of hide and seek. If one does not try to run away and hide when the person is counting, one will be easily found. If one tries to hide behind a small tree, it will take longer to be found but still not long enough to be the winner. Instead, if one disguises oneself with military clothing and hides in a bush one will be hard to find. The drug's journey within the body is similar. During its course of finding its intended receptor, there are obstacles on the way trying to degrade this foreign object in the body and get rid of it. However, the drug can be modified in such a way that it takes longer for it to be degraded and even be disguised to be in the body long enough to find its intended target.
The last puzzle piece can be described as turning on a flashlight. To turn the flashlight on it needs to have a specific battery inserted. The battery needs to be of the right size and needs to be put in the right direction for the circuit to be complete and turn the light on. It is the same for the drug. It needs to be of the right size and to fit in a specific direction to be able to either activate or deactivate the receptor depending on its intent.
Building this puzzle is a difficult task because the puzzle does not come with instructions, and it does not come in a box with designated pieces. These pieces need to be handmade, and the instructions need to be written along the way. However, with one piece at a time, it is making its way to completion. In this thesis, 12 new compounds have successfully been made with the purpose to gain further understanding of how the molecule-protein interactions work in this specific receptor system. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9182853
- author
- Peltomaa, Klara LU
- supervisor
- organization
- course
- KEMR45 20242
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Organic chemistry, NMDA receptors, Potential drugs
- language
- English
- id
- 9182853
- date added to LUP
- 2025-01-31 07:42:46
- date last changed
- 2025-01-31 07:42:46
@misc{9182853,
abstract = {{NMDA receptors are part of the family iGluRs that regulate the flow of positive ions, such as Na+, K+ and Ca2+, by ligand gating. Upon activation with Glutamate, the channel opens, and a flowthrough of ions occurs. NMDA receptors are unique in that they require the co-agonist glycine for activation and that they exhibit voltage-dependent ion flow due to Mg2+ blockade. The NMDA receptors have three subtypes, GluN1, GluN2 and GluN3 which in turn have subunits of their own. The NMDA receptors are constructed with two GluN1 subunits together with two GluN2 and/or GluN3 subunits. The GluN1/2 receptors are more important from a physiological perspective; thus, these receptors are the focus of this thesis, specifically GluN1/2A and GluN1/2B.
The NMDA receptors are known for their role in excitotoxicity, which make them important targets for potential drugs against e.g. Parkinson’s disease and Huntignson’s disease. It has been proven difficult in making potent drugs for the NMDA receptors due to the high risk of side effects. The reason for this is that the different subtypes of the NMDA receptors are similar in structure but also that they are widely spread across the brain, thus targeting only one receptor is challenging.
TCN213 is a scaffold that is selective for the GluN1/2A receptor with sufficient potency, binding at the interface, and able to cross the blood brain barrier. However, research on improving its potency and metabolism is ongoing. Different amide bioisostere analogues of the TCN213 scaffold have been synthesized to explore the amide part of this scaffold and study its importance in TCN213s activity. Important information of non-conserved amino acids between the subtypes GluN1/2A and GluN1/2B, specifically a switch from valine 267 to phenylalanine 262 respectively, have highlighted the theory behind the synthesis of the GluN1/2B analogues. Different synthetic approaches have been used to synthesize potential NAMs for the GluN1/2A and GluN1/2B receptors. However, their activity is yet to be determined.}},
author = {{Peltomaa, Klara}},
language = {{eng}},
note = {{Student Paper}},
title = {{Discovery of Selective Ligands for the Modulation of NMDA Receptors}},
year = {{2025}},
}