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  • Final Activity and Management Report Summary - D2R ANTAGONIST (Identification of novel selective Dopaminergic Receptor 2-beta arrestin antagonist: involvement in schizophrenia treatment)

Final Activity and Management Report Summary - D2R ANTAGONIST (Identification of novel selective Dopaminergic Receptor 2-beta arrestin antagonist: involvement in schizophrenia treatment)

G Protein-Coupled Receptors (GPCR) are proteins expressed on every cells and control different functions in the body. These GPCR have been identified in central nervous system (CNS), cardiovascular and gastrointestinal diseases resulting in enhanced understanding of the pathologic basis of disease, new diagnostics and new drugs. They are targets for around 50% of current therapeutics. A better understanding of the biochemical function of these receptors and the action of compounds used in clinic targeting them is of huge interest to identify new compounds more specific and with poor side effects. During the Marie Curie fellowship, my work was focused on two main GPCRs: the dopamine D2 receptor and the apelin receptor. The dopaminergic D2 receptor (D2R) controls, in the brain, a myriad of functions such as movement, emotions and learning. Dysregulation of D2R signalling is involved in schizophrenia and Parkinson's disease.

Schizophrenia is a severe and chronic mental illness. Different therapeutic agents are used to treat schizophrenic patients but the new generation of antipsychotic drugs has remained elusive and certain side effects can still impact patient health and quality of life. Thus, the first aim of my project was to characterise the activity of the different generation of antipsychotics used in clinic on two essential biochemical pathways controlled by D2R inside the neurons, named the G-protein and the beta-arrestin dependent pathways. By using different tools and technologies, we were able to show that, in vitro, all antipsychotics share a common property, they uniformly and more potently block the beta-arrestin pathway downstream of the D2 dopamine receptor compared to the G-protein dependent pathway.

This unexpected result is of great interest since it provides an exciting avenue of research for the design of new drugs that would inhibit specifically this pathway and thus could induce fewer side effects, one of the major problems for the compounds actually used. The second part of this project aimed to validate these results on genetically engineered mouse models that recapitulate schizophrenic patients' symptoms. For this purpose, we looked at the state of activation of different proteins downstream the G-protein and the beta-arrestin pathways in different brain regions before and after treatment with different antipsychotics. Our data clearly showed that the different antipsychotics present different profiles of activity in the different mouse models used and we were not able to confirm in vivo the results obtained in vitro. In fact, this goal is more difficult to achieve since antipsychotics act on several receptors and not only D2R. Another GPCR of great interest is the apelin receptor which is involved in the development of new blood vessels also called neoangiogenesis. This receptor can be activated by its natural ligand named apelin.

Angiogenesis is important for physiological development. Nevertheless, neoangiogenesis plays a central role in pathological conditions such as tumour growth or Age related Macular Disease (AMD). Our group has already shown that apelin is over expressed in one-third of the human tumours and with a very high frequency in Human pancreatic cancer. Thus, this receptor represents a newly identified target in order to inhibit neoangiogenesis and block tumour development. Our aim was to search and characterise molecules which could block apelin receptor and thus could be used as anti-angiogenic and/or antitumor compounds. Using a microscopy approach, we screened different chemical libraries. With our screen, we have been able to identify two compounds. Our efforts have been focused on one of these two molecules since this compound is already used in clinic. We confirmed first that this compound act directly on the apelin receptor and we then started to characterise its pharmacological properties. We also showed that this molecule blocks tumour development and angiogenesis.

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