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Canna~Fangled Abstracts

Identification and Characterization of Cannabidiol as an OX1R Antagonist by Computational and In Vitro Functional Validation

By August 1, 2021August 30th, 2021No Comments
. 2021 Aug 1;11(8):1134.

doi: 10.3390/biom11081134.

Rosa Maria Vitale 1, Fabio Arturo Iannotti 1 2, Aniello Schiano Moriello 2 3, Lea Tunisi 2 4, Fabiana Piscitelli 1 2, Ranjev Savopoulos 5, Luigia Cristino 1 2, Luciano De Petrocellis 1 2, Pietro Amodeo 1, Roy Gray 5, Vincenzo Di Marzo 1 2 6
Affiliations 

Abstract

The potential, multifaceted therapeutic profile of cannabidiol (CBD), a major constituent derived from the Cannabis sativa plant, covers a wide range of neurological and psychiatric disorders, ranging from anxiety to pediatric epilepsy and drug addiction. However, the molecular targets responsible for these effects have been only partially identified. In this view, the involvement of the orexin system, the key regulator in arousal and the sleep/wake cycle, and in motivation and reward processes, including drug addiction, prompted us to explore, using computational and experimental approaches, the possibility that CBD could act as a ligand of orexin receptors, orexin 1 receptor of type 1 (OX1R) and type 2 (OX2R). Ligand-binding assays showed that CBD is a selective ligand of OX1R in the low micromolar range (Ki 1.58 ± 0.2 μM) while in vitro functional assays, carried out by intracellular calcium imaging and mobilization assays, showed that CBD acts as an antagonist at this receptor. Finally, the putative binding mode of CBD has been inferred by molecular docking and molecular dynamics simulations and its selectivity toward the OX1R subtype rationalized at the molecular level. This study provides the first evidence that CBD acts as an OX1R antagonist, supporting its potential use in addictive disorders and/or body weight regulation.

 

Keywords: calcium mobilization assay, cannabidiol, molecular docking, molecular dynamics, orexin receptors

Conflict of interest statement

R.M.V., F.A.I., F.P., L.C. and V.D. receive funding from GW Research Ltd., UK. R.G. and R.S. are employees of GW Research Ltd., UK. V.D. is a paid consultant to GW Research Ltd., UK.

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