Novel ligands for the human adenosine A1 receptor

Chang, L.C.W. (2005)

Doctoral Thesis

This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family.

• Adenosine receptors
• Biological evaluation
• Development
• Ligands
• Medicinal Chemistry
• Synthesis

• All authors: Chang, L.C.W.
• Supervisor: IJzerman, A.P.
• Co-supervisor: Brussee, J.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Science, Leiden University
• Date: 2005-12-08
• Publisher: Faculty of Mathematics and Natural Sciences, Leiden University, Leiden University