DESIGN OF HIGH-AFFINITY LIGANDS FOR THE BENZOTHIADIAZINE ALLOSTERIC BINDING SITE OF THE AMPA RECEPTORS

L-glutamic acid is the major excitatory neurotransmitter in the brain. It exerts its effects through metabotropic and ionotropic receptors. Among the latter, three subtypes have been identified: NMDA, AMPA and KA receptors. It is now well established that a deficit in glutamatergic signaling may be responsible for neurological disorders such as mild cognitive impairment, schizophrenia, depression, and ADHD. Enhancement of the signal through positive allosteric modulators of AMPA receptors might be a therapeutic issue for these diseases. These compounds are expected to exert a fine tuning of the signal. Since they require the presence of the endogenous ligand to be active, they are expected to induce less toxicity than agonists.
In this context, based on the structure of known allosteric modulators of AMPA receptors such as cyclothiazide and IDRA 21, the Laboratory of Medicinal Chemistry (University of Liège) has developed a series of 1,2,4-benzothiadiazine 1,1-dioxides with high potency as AMPA receptor potentiators. Crystallographic data obtained by the Department of Drug Design and Pharmacology (University of Copenhagen) highlighted those potentiators bind to two contiguous sites at the dimer interface of the ligand binding domain (LBD) of the AMPA receptor1,2. Based on these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity. This assumption was reinforced by docking experiments conducted with virtual examples of dimeric compounds on the GluA2-LBD (collaboration with NAMEDIC).
The present work is thus focusing on the preparation of a family of dimeric benzothiadiazine dioxides. Moreover, in collaboration with GIGA-Molecular Pharmacology, we are developing a pharmacological in vitro assay based on the measurement of Ca2+ inflow through a fluorimetric method. This medium-throughput screening will enable the characterization of our new compounds and the validation of our working hypothesis.