Non-ribose ligands for the human adenosine A1 receptor

Klaasse, E.C. (2008)

Doctoral Thesis

This thesis describes new, non-ribose ligands for the human Adenosine A1 Receptor (hA1R). An introduction to the four adenosine receptors subtypes, their history and cloning, occurrence, functioning, trafficking and therapeutic potential is given in Chapter 1. The process of desensitization and internalization of adenosine receptors in cell systems, tissues and in vivo studies is described in Chapter 2. An overview of the current literature concerning desensitization and internalization of the adenosine receptors is given and the regulation of the different subtypes upon agonist binding is discussed. In Chapter 3, human adenosine A1 receptors fused to 351Cys mutated Gi_-subunits are used as tools to study inverse agonism. In addition, the enhancing effect of the allosteric modulator PD81,723 on agonist affinity is shown. The influence of allosteric modulators on the internalization of the A1R is detailed in Chapter 4. The synthesis, affinity and activity of twelve non-ribose ligands, all ___2-amino-4-(3 and/or 4-disubstituted phenyl)-6-(substituted)sulfanyl-pyridine-3,5-dicarbonitriles, are described in Chapter 5. Chapter 6 evaluates the characteristics of LUF6037 a representative of these 3,4-methylenedioxyphenyl substituted compounds. One of the other non-ribose agonists with high affinity for the A1R, LUF5834, was chosen to be radioactively labelled. Chapter 7 describes the evaluation of [3H]LUF5834 as a new agonist radioligand.

• Activity
• Affinity
• Allosteric modulation
• Human Adenosine A1 Receptor
• Internalization
• Non-ribose ligands

• All authors: Klaasse, E.C.
• Supervisor: IJzerman, A.P.; Grip, W.J. de
• Co-supervisor: Beukers, W.M.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Science, Leiden University
• Date: 2008-06-10