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

• Published in: Journal of medicinal chemistry 1992-09, Vol.35 (18), p.3319-3324
• Main Authors: McQuaid, Loretta A, Smith, Edward C. R, South, Kimberly K, Mitch, Charles H, Schoepp, Darryle D, True, Rebecca A, Calligaro, David O, O'Malley, Patrick J, Lodge, David, Ornstein, Paul L
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Chemistry; Exact sciences and technology; Glycine - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Ibotenic Acid - analogs & derivatives; Ibotenic Acid - antagonists & inhibitors; Male; Organic chemistry; Preparations and properties; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Quinoxalines - chemical synthesis; Quinoxalines - pharmacology; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, Neurotransmitter - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• 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 microM and antagonized 40 microM AMPA-induced depolarization in the cortical slice preparation with an IC50 of 44 microM. 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 microM, 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.