Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173

A seires of 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylat es analogues of TQX-173 (1b), bearing different nitrogen-containing heteroc ycles at position-8, were synthesized as AMPA receptor antagonists. All the reported compounds were also biologically evaluated for their binding at g lycine/NMDA and KA receptors to better assess their selectivity toward the AMPA receptor. Structure-activity relationships (SAR) on these TQX derivati ves have evidenced that the precise positioning of the nitrogen atoms and t he specific electronic topography of the 8-heteroaromatic ring are both imp ortant for the anchoring to the AMPA receptor. In fact, it has been well-es tablished that the presence of a N-3-nitrogen-containing heterocycle at pos ition-8 of the TQX framework is an essential feature for potent and selecti ve AMPA receptor antagonists. Functional antagonism at both AMPA receptor a nd NMDA receptor-ion channel complex was evaluated by assessing the ability of some selected compounds to inhibit depolarization induced by 5 muM AMPA or NMDA in mouse cortical wedge preparations.