1. Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system
- Author
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Simone Bertini, Francesca Gado, Maurizio Bifulco, Margherita Lapillo, Mario Abate, Elena Ciaglia, Tiziano Tuccinardi, Marco Macchia, Giulio Poli, Maria Digiacomo, Chiara Arena, Clementina Manera, Andrea Chicca, Jürg Gertsch, Chicca, Andrea, Arena, Chiara, Bertini, Simone, Gado, Francesca, Ciaglia, Elena, Abate, Mario, Digiacomo, Maria, Lapillo, Margherita, Poli, Giulio, Bifulco, Maurizio, Macchia, Marco, Tuccinardi, Tiziano, Gertsch, Jürg, and Manera, Clementina
- Subjects
0301 basic medicine ,Cannabinoid receptor ,Endocannabinoid system ,Pyridines ,Polypharmacology ,Pyridine ,Pharmacology ,Inhibitory postsynaptic potential ,Partial agonist ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,U937 lymphoblastoid cell ,Drug Discovery ,Tumor Cells, Cultured ,Inverse agonist ,Cytotoxic T cell ,Humans ,610 Medicine & health ,Cannabinoid receptors ,Receptors, Cannabinoid ,Endocannabinoid ,U251MG glioblastoma cell line ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Antagonist ,General Medicine ,Anandamide ,U937 Cells ,Molecular Docking Simulation ,030104 developmental biology ,Molecular docking ,570 Life sciences ,biology ,030217 neurology & neurosurgery ,U937 lymphoblastoid cells ,Endocannabinoids ,Human - Abstract
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.
- Published
- 2018