Antagonist, Partial Agonist, and Full Agonist Imidazo[1,5-a]quinoxaline Amides and Carbamates Acting through the GABAA/Benzodiazepine Receptor

• Published in: Journal of medicinal chemistry Vol. 37; no. 6; pp. 758 - 768
• Main Authors: TenBrink, Ruth E, Im, Wha B, Sethy, Vimala H, Tang, Andrew H, Carter, Don B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.1994
• Subjects: Animals; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - metabolism; Cells, Cultured; GABA Antagonists; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - metabolism; Rats; Receptors, GABA - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00032a008

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihyd roimidazo[1,5- a]pyrrolo[2,1-c]quinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5- dihydroimidazo[1,5-a]quinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazo[1,5-a]pyrrolo[2,1- c]quinoxaline-1-carboxylate (1e), as well as other imidazo[1,5-a]quinoxaline amides and carbamates, represent a new series of compounds which bind with high affinity to the GABAA/benzodiazepine receptor. These compounds exhibit a wide range of intrinsic efficacies as measured by [35S]TBPS binding ratios. The synthesis of 1a begins with the addition of DL-glutamic acid to 1-fluoro-2-nitrobenzene, followed by reduction of the nitro group and subsequent ring closure to form 3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinoxalin-2-one, followed by a second ring closure to afford (4RS)-1,5-dioxo-1,2,3,4,5,6-hexahydropyrrolo[1,2-a]quinoxali ne as the key intermediate. Appendage of a substituted imidazo ring via the anion of 5-cyclopropyl-1,2,4-oxadiazol-3-yl gives 1a. The (-)- and (+)-isomers of 1a were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for the [3H]flunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.