Universiteit Leiden

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Research project

Covalent inhibitors of G protein-coupled receptors: the case of adenosine receptors

Supervisor: Xue Yang

Daan van der Es

G protein-coupled receptors (GPCRs) are cell membrane-bound proteins that are activated by many of the body’s hormones and neurotransmitters.  As one of them, adenosine receptors are made up of four subtypes, coined A 1R, A 2AR, A 2BR, and A 3R. Activated by the endogenous ligand adenosine, they are primarily coupled to the enzyme adenylate cyclase via their cognate G proteins. Activation of A 1 and A 3 receptors leads to inhibition of adenylate cyclase by a G i protein, whereas A 2A and A 2B receptors stimulate the enzyme through a G S protein. From a drug discovery perspective, the wide distribution of adenosine receptors in mammalian cell types renders it mandatory to search for high-affinity and highly subtype-selective agonists and antagonists, which has been achieved reasonably well with the compounds currently available (all antagonists). More recently, it is increasingly realized that next to good affinity, the duration of receptor occupancy is important for drug efficacy. This receptor occupancy has been termed the drug target residence time. With this perspective, the longest possible residence time has the potential benefit of creating further or additional subtype selectivity.

To design the covalent ligands, expertise of the fundamental mechanisms of how the reactive groups bind to the target offers the means to intelligently design a successful covalent ligand with better affinity. Choosing the correct functional groups that can react with the chemical groups available on target molecules paves the road for successful design. Therefore, designing and synthesizing “safe” covalent drugs by introducing a series of electrophilic groups will be explored as a strategy to identify covalent inhibitors of the adenosine receptors.

The synthesized compounds be evaluated for their affinity, selectivity and degree of covalent binding. The most promising compounds will then be evaluated on wild-type and mutant adenosine receptors to determine the site of attachment. 


  • Organic synthesis operation
  • Cell culture
  • Radioligand binding assays

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