Synthesis and evaluation of N₁-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK₂) receptor ligands

A novel synthetic approach towards N₁-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-prophyl-1,4-benzodiazepine template was carried out on the N₁-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK₂) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK₂ (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg^-1 in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.