Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity. 1. Optimization of the Agonist “Trigger”
- 1 January 1996
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 39 (2) , 562-569
- https://doi.org/10.1021/jm950626d
Abstract
Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.Keywords
This publication has 15 references indexed in Scilit:
- DAMGO, a μ‐opioid receptor selective agonist, distinguishes between μ‐ and δ‐opioid receptors around their first extracellular loopsFEBS Letters, 1995
- Locating ligand-binding sites in 7tm receptors by protein engineeringCurrent Opinion in Biotechnology, 1994
- The Seventh Transmembrane Domain of Gastrin/CCK Receptors Contributes to Nonpeptide Antagonist BindingBiochemical and Biophysical Research Communications, 1994
- STRUCTURE AND FUNCTION OF G PROTEIN-COUPLED RECEPTORSAnnual Review of Biochemistry, 1994
- Biological actions of cholecystokininPeptides, 1994
- Peptidomimetics for Receptor Ligands—Discovery, Development, and Medical PerspectivesAngewandte Chemie International Edition in English, 1993
- A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonistsNature, 1993
- Development of CCK-tetrapeptide analogs as potent and selective CCK-A receptor agonistsJournal of Medicinal Chemistry, 1990
- Rationale for the synthesis and preliminary biological evaluation of highly active new antitumor nitrosoureido sugarsJournal of Medicinal Chemistry, 1989
- A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceusScience, 1985