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

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; Manera, Clementina (2018). Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system. European journal of medicinal chemistry, 154, pp. 155-171. Elsevier 10.1016/j.ejmech.2018.05.019

[img] Text
Polypharmacological.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

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 (K = 23.1 nM, partial agonist) and CB2R (K = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC = 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 IC 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.

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:

Chicca, Andrea, Gertsch, Jürg


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








Barbara Franziska Järmann-Bangerter

Date Deposited:

20 Mar 2019 15:58

Last Modified:

05 Dec 2022 15:25

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Cannabinoid receptors Endocannabinoid system Molecular docking Polypharmacology U251MG glioblastoma cell line U937 lymphoblastoid cells





Actions (login required)

Edit item Edit item
Provide Feedback