Enhancing Action of Positive Allosteric Modulators through the Design of Dimeric Compounds

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 cocrystallized with the GluA2
ligand-binding domain (LBD), a molecular modeling approach was performed
to predict the preferred dimeric combinations. Two 6,6-ethylene-linked
dimeric BTD compounds (16 and 22) 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 22 [6,6′-(ethane-1,2-diyl)­bis­(4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide], with an EC50 value of 1.4 nM. As a proof of concept, the bis-4-methyl-substituted
dimeric compound 16 (EC50 = 13 nM) was successfully
cocrystallized with the GluA2o-LBD and was found to occupy
the two BTD binding sites at the LBD dimer interface.