Synthesis and excitatory amino acid pharmacology of a series of heterocyclic-fused quinoxalinones and quinazolinones

Article abstract of DOI:10.1021/jm00096a002

As part of our program aimed at the development of potent excitatory amino acid antagonists, we synthesized and evaluated a series of substituted 1,2,4- triazolo[4,3-a]quinoxalin-4(5H)-ones, 4, tetrazolo[1,5-a]quinoxalin-4(5H)- ones, 5, and pyrazolo[1,5-c]quinazolin-5(6H)-ones, 6, and an imidazo[1,2- a]quinoxalin-4(5H)-one, 7. In general, the same heterocycles which demonstrated the best affinity for the AMPA receptor also demonstrated the best affinity for the glycine site on the NMDA receptor complex. 1-Propyl- 7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one, 4d, was found to bind with the greatest affinity to the AMPA receptor with an IC₅₀ of 0.83 μM and antagonized 40 μM AMPA-induced depolarization in the cortical slice preparation with an IC₅₀ of 44 μM. 7,8-Dichloro-1,2,4-triazolo[4,3- a]quinoxalin-4(5H)-one, 4a, and 7,8-dichloroimidazo[1,2-a]quinoxalin-4(5H)- one, 7, possessed the best affinity for the glycine site with IC₅₀ values of 0.63 and 1.26 μM, respectively. It is noteworthy that the SAR for the heterocyclic compounds did not directly parallel that of known quinoxalinediones (e.g. DNQX, 2, and DCQX, 15) at the AMPA receptor nor that of the kynurenic acids at the glycine site on the NMDA receptor complex.