Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger"

Christopher J. Aquino, Duncan R. Armour, Judd M. Berman, Larry S. Birkemo, Robin A.E. Carr, Dallas K. Croom, Milana Dezube, Robert W. Dougherty, Gregory N. Ervin, Mary K. Grizzle, Julie E. Head, Gavin C. Hirst, Michael K. James, Michael F. Johnson, Laurence J. Miller, Kennedy L. Queen, Thomas J. Rimele, David N. Smith, Elizabeth E. Sugg

Research output: Contribution to journalArticle

90 Scopus citations

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 substituants 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.

Original languageEnglish (US)
Pages (from-to)562-569
Number of pages8
JournalJournal of Medicinal Chemistry
Volume39
Issue number2
DOIs
StatePublished - Jan 19 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Aquino, C. J., Armour, D. R., Berman, J. M., Birkemo, L. S., Carr, R. A. E., Croom, D. K., Dezube, M., Dougherty, R. W., Ervin, G. N., Grizzle, M. K., Head, J. E., Hirst, G. C., James, M. K., Johnson, M. F., Miller, L. J., Queen, K. L., Rimele, T. J., Smith, D. N., & Sugg, E. E. (1996). Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger". Journal of Medicinal Chemistry, 39(2), 562-569. https://doi.org/10.1021/jm950626d