Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands.
3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK1 receptor selectivity to CCK2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties.
Offel
Michael
M
Aston Pharmacy School, Aston University, Birmingham, England.
Lattmann
Pornthip
P
Singh
Harjit
H
Billington
D C
DC
Bunprakob
Yodchai
Y
Sattayasai
Jintana
J
Lattmann
Eric
E
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001570:Benzodiazepinones; D008024:Ligands; D043886:Receptor, Cholecystokinin A