Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Abstract

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described.The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound32(BPAM395) expressingin vitroactivity on AMPARs (EC2x = 0.24 µM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide10(BPAM344).Interestingly, the 4-allyl-substituted thienothiadiazine dioxide27(BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide32and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors.The thieno-analogue36(BPAM279) of the clinically tested S18986 (11) was selected forin vivoevaluation in mice as a cognitive enhancer due to a safer profile than32after massiveper osdrug administration. Compound36was found to increase the cognition performance in mice at low doses (1 mg/kg)per ossuggesting that the compound was well absorbed after oral administration and able to reach the central nervous system.Finally, compound32was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.HighlightsThe study explored AMPA/kainate receptor PAMs belonging to thienothiadiazine dioxidesThe 4-cyclopropyl-substituted compound32was the most potent AMPA receptor modulator4-Allyl substitution improved activity and selectivity for kainate receptorsThe tricyclic compound36expressed cognitive improvementin vivoin miceCompound32was co-crystallized with GluA2-LBD to examine receptor binding modeGraphical abstract