HIGH-AFFINITY ALPHA-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 mino)carbonyl]4,5 -dihydroimidazo[1,5-a]quinoxaline (2, U-91571) away from the benzene r ing. These analogs orient the carbonyl group in the opposite direction of the previously reported full agonist 1-(5-cyclopropyl-1,2,4-oxadia zol-3-yl)-12, imidazo[1,5-a]pyrrolo[2,1-c]quinoxalin-10(11H)-one (3, U -89267). A number of approaches were utilized to form the ''bottom'' r ing of this tetracyclic ring system including intramolecular cyclizati ons promoted by Lewis acids or base, as well as metal-carbenoid condit ions. The size and substitution pattern of the additional. ring was wi dely varied. Analogs within this series had high affinity for the benz odiazepine receptor on the alpha-aminobutyric acid A chloride ion chan nel complex. From TBPS shift and Cl- current assays, the in vitro effi cacy of compounds within this class ranged from antagonists to partial agonists with only 18a identified as a full agonist. Additionally, se veral analogs were quite potent at antagonizing metrazole-induced seiz ures indicating possible anticonvulsant or anxiolytic activity. Unlike 3, analogs in this series did not have high affinity for the diazepam insensitive alpha(6) beta(2) delta(2) subtype. These results suggest that either constraining the carbonyl group away from the benzene ring or the greater planarity that results from the additional cyclic stru cture provides analogs with partial agonist properties and prevents ef fective interaction with the alpha(6) beta(2) delta(2) subtype.