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Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system.
Journal article

Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system.

  • Chicca A Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland.
  • Arena C Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Bertini S Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Gado F Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Ciaglia E Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, Salerno, Italy.
  • Abate M Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, Salerno, Italy.
  • Digiacomo M Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Lapillo M Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Poli G Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019, Siena, Italy.
  • Bifulco M Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131, Naples, Italy.
  • Macchia M Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • Tuccinardi T Department of Pharmacy, University of Pisa, 56126, Pisa, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
  • Gertsch J Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland.
  • Manera C Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: clementina.manera@farm.unipi.it.
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  • 2018-05-25
Published in:
  • European journal of medicinal chemistry. - 2018
Cannabinoid receptors
Endocannabinoid system
Molecular docking
Polypharmacology
U251MG glioblastoma cell line
U937 lymphoblastoid cells
Dose-Response Relationship, Drug
Endocannabinoids
Humans
Molecular Docking Simulation
Molecular Structure
Pyridines
Receptors, Cannabinoid
Structure-Activity Relationship
Tumor Cells, Cultured
U937 Cells
English The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (Ki = 23.1 nM, partial agonist) and CB2R (Ki = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC50 = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC50 = 2.5 μΜ). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC50 values (0.28-0.62 μΜ). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/44415
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