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

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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
StatePublished - Jan 19 1996

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Cholecystokinin A Receptor
Cholecystokinin
Benzodiazepines
Cholecystokinin Receptors
Appetite Depressants
Gallbladder
Registries
Rats
Screening
Guinea Pigs
Nitrogen
Electrons

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Aquino, C. J., Armour, D. R., Berman, J. M., Birkemo, L. S., Carr, R. A. E., Croom, D. K., ... 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.

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger". / Aquino, Christopher J.; Armour, Duncan R.; Berman, Judd M.; Birkemo, Larry S.; Carr, Robin A E; Croom, Dallas K.; Dezube, Milana; Dougherty, Robert W.; Ervin, Gregory N.; Grizzle, Mary K.; Head, Julie E.; Hirst, Gavin C.; James, Michael K.; Johnson, Michael F.; Miller, Laurence J; Queen, Kennedy L.; Rimele, Thomas J.; Smith, David N.; Sugg, Elizabeth E.

In: Journal of Medicinal Chemistry, Vol. 39, No. 2, 19.01.1996, p. 562-569.

Research output: Contribution to journalArticle

Aquino, CJ, Armour, DR, Berman, JM, Birkemo, LS, Carr, RAE, Croom, DK, Dezube, M, Dougherty, RW, Ervin, GN, Grizzle, MK, Head, JE, Hirst, GC, James, MK, Johnson, MF, Miller, LJ, Queen, KL, Rimele, TJ, Smith, DN & Sugg, EE 1996, 'Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger"', Journal of Medicinal Chemistry, vol. 39, no. 2, pp. 562-569.
Aquino, Christopher J. ; Armour, Duncan R. ; Berman, Judd M. ; Birkemo, Larry S. ; Carr, Robin A E ; Croom, Dallas K. ; Dezube, Milana ; Dougherty, Robert W. ; Ervin, Gregory N. ; Grizzle, Mary K. ; Head, Julie E. ; Hirst, Gavin C. ; James, Michael K. ; Johnson, Michael F. ; Miller, Laurence J ; Queen, Kennedy L. ; Rimele, Thomas J. ; Smith, David N. ; Sugg, Elizabeth E. / Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger". In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 2. pp. 562-569.
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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.",
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AU - Hirst, Gavin C.

AU - James, Michael K.

AU - Johnson, Michael F.

AU - Miller, Laurence J

AU - Queen, Kennedy L.

AU - Rimele, Thomas J.

AU - Smith, David N.

AU - Sugg, Elizabeth E.

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N2 - 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.

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