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

doi:10.1021/jm950626d

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

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

92 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 language	English (US)
Pages (from-to)	562-569
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	39
Issue number	2
DOIs	https://doi.org/10.1021/jm950626d
State	Published - 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

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. https://doi.org/10.1021/jm950626d

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

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.",

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

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AU - Birkemo, Larry S.

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AU - Dougherty, Robert W.

AU - Ervin, Gregory N.

AU - Grizzle, Mary K.

AU - Head, Julie E.

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.

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

Abstract

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