High-Affinity α-Aminobutyric Acid A/Benzodiazepine Ligands: Synthesis and Structure−Activity Relationship Studies of a New Series of Tetracyclic Imidazoquinoxalines†

A series of tetracyclic imidazoquinoxaline analogs was developed which constrain the carbonyl group of the partial agonist 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-[(dimethylamino)carbonyl]-4,5-dihydroimidazo[1,5-a]quinoxaline (2, U-91571) away from the benzene ring. These analogs orient the carbonyl group in the opposite direction of the previously reported full agonist 1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazo[1,5-a]pyrrolo[2,1-c]quinoxalin-10(11H)-one (3, U-89267). A number of approaches were utilized to form the “bottom” ring of this tetracyclic ring system including intramolecular cyclizations promoted by Lewis acids or base, as well as metal−carbenoid conditions. The size and substitution pattern of the additional ring was widely varied. Analogs within this series had high affinity for the benzodiazepine receptor on the α-aminobutyric acid A chloride ion channel complex. From TBPS shift and Cl- current assays, the in vitro efficacy of compounds within this class ranged from antago...