title: Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands.
abstract: 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-propyl-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.
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK. e.lattmann@aston.ac.uk
authors.forename: Eric
authors.initials: E
authors.lastname: Lattmann
authors.forename: Jintana
authors.initials: J
authors.lastname: Sattayasai
authors.forename: David C
authors.initials: DC
authors.lastname: Billington
authors.forename: David R
authors.initials: DR
authors.lastname: Poyner
authors.forename: Prapawadee
authors.initials: P
authors.lastname: Puapairoj
authors.forename: Siriporn
authors.initials: S
authors.lastname: Tiamkao
authors.forename: Wanchai
authors.initials: W
authors.lastname: Airarat
authors.forename: Harjit
authors.initials: H
authors.lastname: Singh
authors.forename: Michael
authors.initials: M
authors.lastname: Offel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001274:Atmospheric Pressure; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D015394:Molecular Structure; D011869:Radioligand Assay; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines