L-glutamate, the key excitatory neurotransmitter in the central nervous system, exerts its biological effect through the activation of either metabotropic (mGluRs, G protein-coupled) or ionotropic (iGluRs, ligand-gated ion channel) receptors. Among iGluRs, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is recognized as a promising biological target for the development of either probing pharmacological tools or novel drug candidates for the treatment of brain disorders such as attention deficit hyperactivity disorder, Alzheimer’s disease, mild depression or schizophrenia. The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs co-crystallized with the GluA2o ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2o(Q) (calcium flux experiment). These compounds were found to be about 10,000 times more potent than their respective monomers, the most active dimeric compound being the bis-4-cyclopropyl-substituted compound with an EC50 value of 1.4 nM. As a proof of concept, the two dimeric compounds were successfully co-crystallized with the GluA2o-LBD and were found to occupy the two BTD binding sites at the LBD dimer interface.

Enhancing potency of AMPA receptor positive allosteric modulators through the design of dimeric compounds

2019 Fall National Meeting

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