Antagonist, Partial Agonist, and Full Agonist Imidazoquinoxaline Amides and Carbamates Acting through the GABAA/benzodiazepine Receptor

Article abstract of DOI:10.1021/jm00032a008

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazo<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 GABA_A/benzodiazepine receptor.These compound 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>quinoxaline 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 <3H>flunitrazepam binding site with K_i's of 0.87, 0.62, and 0.65 nM, respectively.