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

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