Design, synthesis and pharmacological evaluation of dimeric ligands for the benzothiadiazine dioxide 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 schizophrenia, depression, mild cognitive impairment 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 (1) and IDRA 21 (2), 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, among which compounds (3) and (4). Crystallographic data obtained by the Department of Medicinal Chemistry (University of Copenhagen) highlighted that (3) and (4) bind to two contiguous sites at the dimer interface of the ligand binding domain of the AMPA receptor1,2. From these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity.
Our work consists in the development of a family of dimeric benzothiadiazine dioxides and their evaluation in a pharmacological assay. Several structural parameters such as the position of the bridge on the aromatic ring between the two heterocycles as well as its nature and length will be studied in order to determine their impact on the activity and thus the affinity.