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

Eric Lattmann*, Jintana Sattayasai, David C. Billington, David R. Poyner, Prapawadee Puapairoj, Siriporn Tiamkao, Wanchai Airarat, Harjit Singh, Michael Offel, David Poyner

*Corresponding author for this work

Research output: Contribution to journalArticle

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-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.

Original languageEnglish
Pages (from-to)827-834
Number of pages8
JournalJournal of Pharmacy and Pharmacology
Volume54
Issue number6
DOIs
Publication statusPublished - 24 Jun 2002

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