Positive Allosteric Modulation of CB1 and CB2 Cannabinoid Receptors Enhances the Neuroprotective Activity of a Dual CB1R/CB2R Orthosteric Agonist

• Main Authors: Beatrice Polini, Chiara Cervetto, Sara Carpi, Simone Pelassa, Francesca Gado, Rebecca Ferrisi, Simone Bertini, Paola Nieri, Manuela Marcoli, Clementina Manera
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Life
• Subjects: endocannabinoids system; cannabinoid receptor type 2; cannabinoid receptor type 1; positive allosteric modulator; microglial cell; glutamate release
• Online Access: https://www.mdpi.com/2075-1729/10/12/333
• ISSN: 2075-1729

Preclinical studies highlighted that compounds targeting cannabinoid receptors could be useful for developing novel therapies against neurodegenerative disorders. However, the chronic use of orthosteric agonists alone has several disadvantages, limiting their usefulness as clinically relevant drugs. Positive allosteric modulators might represent a promising approach to achieve the potential therapeutic benefits of orthosteric agonists of cannabinoid receptors through increasing their activity and limiting their adverse effects. The aim of the present study was to show the effects of positive allosteric ligands of cannabinoid receptors on the activity of a potent dual orthosteric agonist for neuroinflammation and excitotoxic damage by excessive glutamate release. The results indicate that the combination of an orthosteric agonist with positive allosteric modulators could represent a promising therapeutic approach to the treatment of neurodegenerative disorders.