Antagonist, Partial Agonist, and Full Agonist Imidazo1,5-aquinoxaline Amides and Carbamates Acting through the GABAA/Benzodiazepine Receptor

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihyd roimidazo1,5- apyrrolo2,1-cquinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5- dihydroimidazo1,5-aquinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazo1,5-apyrrolo2,1- cquinoxaline-1-carboxylate (1e), as well as other imidazo1,5-aquinoxaline 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 35STBPS 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-hexahydropyrrolo1,2-aquinoxali 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 3Hflunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.