Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors

Serena Pasquini, Maria De Rosa, Alessia Ligresti, Claudia Mugnaini, Antonella Brizzi, Nicola P. Caradonna, Maria Grazia Cascio, Daniele Bolognini, Roger G. Pertwee, Vincenzo Di Marzo, Federico Corelli*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Within our studies on structure activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CBI) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K-i(CB1) and K-i(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl) amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CBI receptor. Compounds 4 and 40, a CB2 and a CBI ligand, respectively, behaved as partial agonists in the [S-35]GTP gamma S assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood brain barrier. (C) 2012 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
Pages (from-to)30-43
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume58
Early online date3 Oct 2012
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Synthesis
  • Quinolones
  • Cannabinoid ligands
  • Partial agonists
  • Peripheral ligands
  • SELECTIVE ANTAGONIST
  • POTENT
  • AGONISTS
  • CB1
  • IDENTIFICATION
  • QUINOLONES
  • DESIGN

Cite this

Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. / Pasquini, Serena; De Rosa, Maria; Ligresti, Alessia; Mugnaini, Claudia; Brizzi, Antonella; Caradonna, Nicola P.; Cascio, Maria Grazia; Bolognini, Daniele; Pertwee, Roger G.; Di Marzo, Vincenzo; Corelli, Federico.

In: European Journal of Medicinal Chemistry, Vol. 58, 12.2012, p. 30-43.

Research output: Contribution to journalArticle

Pasquini, Serena ; De Rosa, Maria ; Ligresti, Alessia ; Mugnaini, Claudia ; Brizzi, Antonella ; Caradonna, Nicola P. ; Cascio, Maria Grazia ; Bolognini, Daniele ; Pertwee, Roger G. ; Di Marzo, Vincenzo ; Corelli, Federico. / Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. In: European Journal of Medicinal Chemistry. 2012 ; Vol. 58. pp. 30-43.
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abstract = "Within our studies on structure activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CBI) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K-i(CB1) and K-i(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl) amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CBI receptor. Compounds 4 and 40, a CB2 and a CBI ligand, respectively, behaved as partial agonists in the [S-35]GTP gamma S assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood brain barrier. (C) 2012 Elsevier Masson SAS. All rights reserved.",
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author = "Serena Pasquini and {De Rosa}, Maria and Alessia Ligresti and Claudia Mugnaini and Antonella Brizzi and Caradonna, {Nicola P.} and Cascio, {Maria Grazia} and Daniele Bolognini and Pertwee, {Roger G.} and {Di Marzo}, Vincenzo and Federico Corelli",
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AU - Pasquini, Serena

AU - De Rosa, Maria

AU - Ligresti, Alessia

AU - Mugnaini, Claudia

AU - Brizzi, Antonella

AU - Caradonna, Nicola P.

AU - Cascio, Maria Grazia

AU - Bolognini, Daniele

AU - Pertwee, Roger G.

AU - Di Marzo, Vincenzo

AU - Corelli, Federico

N1 - Acknowledgements Authors wish to thank Dr. Elisa Turlizzi (Siena Biotech SpA, Siena, Italy) for helpful discussions and Mr Marco Allarà (CNR, Pozzuoli) and Mrs Lesley A. Stevenson (University of Aberdeen) for technical support.

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N2 - Within our studies on structure activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CBI) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K-i(CB1) and K-i(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl) amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CBI receptor. Compounds 4 and 40, a CB2 and a CBI ligand, respectively, behaved as partial agonists in the [S-35]GTP gamma S assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood brain barrier. (C) 2012 Elsevier Masson SAS. All rights reserved.

AB - Within our studies on structure activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CBI) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K-i(CB1) and K-i(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl) amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CBI receptor. Compounds 4 and 40, a CB2 and a CBI ligand, respectively, behaved as partial agonists in the [S-35]GTP gamma S assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood brain barrier. (C) 2012 Elsevier Masson SAS. All rights reserved.

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KW - Cannabinoid ligands

KW - Partial agonists

KW - Peripheral ligands

KW - SELECTIVE ANTAGONIST

KW - POTENT

KW - AGONISTS

KW - CB1

KW - IDENTIFICATION

KW - QUINOLONES

KW - DESIGN

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