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Synthesis and Pharmacological Evaluation of Novel Heteroaromatic Ligands of the A1 Adenosine Receptor

Date: 26 October 2010
Author: FB Rice
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FB Rice & Co is delighted to congratulate Chemistry Trainee Attorney Dr Gemma Ferguson on the conferment of her PhD from Monash University. The title of Gemma’s thesis is ‘Synthesis and Pharmacological Evaluation of Novel Heteroaromatic Ligands of the A1 Adenosine Receptor’.
 
The following is a summary of Gemma's thesis:
 
Adenosine is a compound that is produced by cells under stress and it has a protective role within the body.  Adenosine does this through binding to receptors found on the surface of cells throughout the body.  Since adenosine is rapidly metabolized it acts as a local protector, targeting the site of trauma.
 
Selective adenosine receptor ligands have potential therapeutic applications in cardiovascular, inflammatory and neurodegenerative diseases.  Many potent and selective compounds that mimic the behaviour of adenosine have been reported. However, the development of these compounds as therapeutic agents has been limited by side effects.
 
A promising alternative are allosteric modulators.  Allosteric modulators bind to a site on the receptor that is distinct to the binding site of the natural ligand.  Allosteric modulators can either enhance or inhibit the action of the naturally occurring ligand.  This allows us to selectively tune receptor signaling in both a site- and event-specific fashion and harness the local action of adenosine at the site of trauma.
 
At the beginning of her PhD project Gemma was provided with a lead compound that showed promising activity as an allosteric enhancer of the adenosine receptor.  The major part of the project was making analogues of this lead compound to understand which parts of the structure were important for activity.  For some analogues this required the development of new synthetic routes.
 
The activity of test compounds was assessed in pharmacological cell based assays.  The initial results showed that the compounds had the capacity to recognize an allosteric site on the receptor.  However, subsequent assays showed that the majority of compounds also blocked the binding of adenosine at the receptor.
 
To further investigate how these compounds interacted with the adenosine receptor Gemma performed functional assays, which were more likely to reflect physiologically relevant modes of interaction between the test compounds and the receptor.  The results showed that the test compounds were blocking the binding of adenosine by interaction with the adenosine binding site and not through an allosteric site.  Only a very low amount of compound was required to block adenosine binding, showing that Gemma had developed a potent antagonist of the adenosine receptor.
 
Compounds that block the binding of adenosine in the central nervous system have been reported to improve memory performance and may prove useful for disorders such as Alzheimer’s disease.
 
The remainder of the project attempted to understand the structural relationships between allosteric modulation and blocking adenosine’s binding at the adenosine receptor.
 

If you have any questions or would like to discuss please email Gemma Ferguson or call on +61 3 8618 4137. 

 
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