Développement de médicaments innovants ciblant les hétéromères des récepteurs couples aux protéines G – MED-HET-REC-2

Depressive disorders have a lifetime prevalence of 10-25% with increasing incidence in older people. Depression accounts for 4.4% of the years lived with disability worldwide, and is expected by 2020 to be the second highest cause of morbidity. Despite significant advances in the understanding and treatment of depression, its causes and molecular basis are still poorly understood and there exists a need to develop more efficient and better-tolerated antidepressants. In 2010, a novel antidepressant, Agomelatine (Valdoxan) has been introduced on the market. Clinical trials have shown that favorable features of Agomelatine are fast onset of the therapeutic effect and the absence of major side effects. This compound represents a novel class of antidepressant as it is the first drug that targets melatonin MT1 and MT2 receptors (agonistic properties) and 5-HT2c receptors (antagonistic properties) all belonging to the G protein-coupled receptor (GPCR) super-family. The unique activity profile of Agomelatine apparently depends on both, the melatonergic and the serotoninergic components. However, the molecular mechanism of this “cross-talk” is currently unknown. In recent years a lot of evidence has accumulated that GPCRs can form homo- and heteromers. Increasing evidence shows that GPCR heteromers can be considered as a distinct functional entity with pharmacological and functional properties different from those of the corresponding homomers. Interestingly, several examples in the literature describe the implication of heteromers in psychiatric disorders. Because of the unique bifunctional (i. e. targeting two different receptors) profile of Agomelatine (melatonin receptor agonist and 5-HT2c receptor antagonist), we hypothesized that Agomelatine might target MT1/5-HT2c or MT2/5-HT2c heteromers and may be responsible for their antidepressant effects.