ANTAGONIST, PARTIAL AGONIST, AND FULL AGONIST IMIDAZO[1,5-A]QUINOXALINE AMIDES AND CARBAMATES ACTING THROUGH THE GABA(A) BENZODIAZEPINE RECEPTOR

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazo[1,5-a]pyrrolo[2,1-c]quinoxaline-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinozaline (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 compounds exhibit a wide range of intrinsic efficacies as measured by [S-35]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 la were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for the [H-3]flunitrazepam binding site with K(i)'s of 0.87, 0.62, and 0.65 nM, respectively.