TrkBDNFarmod

Binding of neurotrophins (NT) to tropomyosin-related kinase (Trk) receptors play a key role in the development and maintenance of central and peripheral nervous systems. Among these NTs, the brain-derived neurotrophic factor (BDNF) specifically binds to the TrkB receptor. BDNF is especially important with regard to its trophic effects on neurons, its contribution to the regulation of synaptic transmission and to neuroplasticity phenomena such as those (i) underlying learning and memory, (ii) triggered by lesions in the peripheral and central nervous systems and (iii) associated with drug addiction. The BDNF-TrkB complex appears thus as an important macromolecular component in physiopathological mechanisms underlying numerous neurodegenerative (Alzheimer’s disease, Parkinson’s disease, lateral amyotrophic sclerosis, etc), neurological (epilepsy, pain, L-Dopa induced dyskinesia, etc) and psychiatric (depression, schizophrenia, addiction) disorders. Unfortunately, to date, very few low molecular-weight TrkB-specific ligands have been developed and characterized. Therefore, elucidating the functional role of the TrkB receptor in physiopathological situations requires indirect strategies (e.g. BDNF or TrkB knockout mice, TrkB antibodies, BDNF or TrkB siRNAs, BDNF infusion, etc) aimed at either blocking or activating the TrkB-induced signalling cascade. Starting from the three-dimensional structure of the BDNF-TrkB 2:2 heterodimer, we have recently identified, by a double virtual screening strategy, several low molecular-weight non-peptide modulators of the TrkB activity (full antagonist, partial agonist, BDNF potentiator). On the other hand, the synthesis of the first antagonist able to cross the blood-brain barrier allowed us to demonstrate that such a compound is pharmacologically active on behaviour (anxiety-related paradigm) and nociception. From these preliminary data, the main objectives of the present project, which involves 4 teams with complementary expertises, are as follows: (i) to synthesize, by using both rational design and medicinal chemistry (systematic structure-activity relationships), novel specific agonists and antagonists with high affinity for TrkB, (ii) to thoroughly characterize their functional properties in validated in vitro (biochemistry, cell biology) and in vivo (pharmacology) assays, and (iii) to use the best of these ligands as novel pharmacological tools for investigating the implications of TrkB in depression-like behaviour and pain signaling (in chronic neuropathic pain) in validated animal models. The project implies the use of a wide range of technical approaches (rational drug design, medicinal chemistry, in vitro biochemistry, in vivo behavioral pharmacology, functional neuroanatomy) highly relevant to a research programme aimed at the development of novel biologically active molecules. Achievement of this programme will allow us to estimate whether or not TrkB ligands have a potential interest in the treatment of diseases for which currently available therapeutic means are both poorly effective and poorly tolerated (for instance: neuropathic pain, fibromyalgia and other idiopathic or “functional” pain disorders). Therefore, further clinical or even industrial developments of our research also are an important goal of our project.