Modification on the 1,2-dihydro-2-oxo-pyridine-3-carboxamide core to obtain multi-target modulators of endocannabinoid system.

Gado, Francesca; Arena, Chiara; Fauci, Cristiana La; Reynoso-Moreno, Ines; Bertini, Simone; Digiacomo, Maria; Meini, Serena; Poli, Giulio; Macchia, Marco; Tuccinardi, Tiziano; Gertsch, Jürg; Chicca, Andrea; Manera, Clementina (2020). Modification on the 1,2-dihydro-2-oxo-pyridine-3-carboxamide core to obtain multi-target modulators of endocannabinoid system. Bioorganic chemistry, 94, p. 103353. Elsevier 10.1016/j.bioorg.2019.103353

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Several preclinical evidence indicate that the modulation of the endocannabinoid system (ECS) represents a promising therapeutic approach for different diseases. However, only few modulators of this system have reached so far an advanced stage of clinical development, mainly due to limited efficacy and CB1 receptor-dependent side effects. Those limitations might be overcome by multi-target compounds that exert pro-cannabinoid activities through the modulation of two or more targets in the ECS. This approach can offer a safer and more effective pharmacological strategy as compared to the modulation of a single target. In this work, we report the synthesis and biological characterization of new 6-aryl-1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives. Our results identified several compounds exhibiting interesting multi-target profiles within the ECS. In particular, compound B1 showed moderate-to-high affinity for cannabinoid receptors (Ki CB1R = 304 nM, partial agonist, Ki CB2R = 3.1 nM, inverse agonist) and a potent inhibition of AEA uptake (IC50 = 62 nM) with moderate inhibition of FAAH (IC50 = 2.9 μM). The corresponding 2-alkoxypyridine analogue B14 exhibited significant inhibitor activity on both FAAH (IC50 = 69 nM) and AEA uptake (IC50 = 76 nM) without significantly binding to both cannabinoid receptor subtypes. Molecular docking analysis was carried out on the three-dimensional structures of CB1R and CB2R and of FAAH to rationalize the structure-activity relationships of this series of compounds.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Reynoso, Ines del Carmen; Gertsch, Jürg and Chicca, Andrea


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health








Barbara Järmann-Bangerter

Date Deposited:

11 Nov 2019 11:29

Last Modified:

10 Jan 2020 01:32

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Anandamide cellular uptake Cannabinoid receptors Endocannabinoid system Fatty acid amide hydrolase Multitarget α/β-Hydrolase domain




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