Title:Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases
Volume: 10
Issue: 2
Author(s): Andrea Chicca, Chiara Arena and Clementina Manera
Affiliation:
Keywords:
Endocannabinoid system, endocannabinoid, anandamide, 2-arachidonoyl glycerol, FAAH, MAGL, cannabinoid
receptors.
Abstract: Background: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids
which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid
receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and
pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many
potent and selective ligands for cannabinoid receptors have been generated over the last two decades,
this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1-
mediated side effects.
Methods: The compounds and results presented in this review article have been gathered from an extensive research in
public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry
numbers, websites and scientific articles is provided in the text and/or in the reference section.
Results: Over the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase
(FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized
and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid
system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid
membrane transporter have been described in the literature. Polypharmacological approaches which combine
mild or reversible inhibition of at least two of these targets are also under investigation.
Conclusions: The ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The
modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on
the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL,
ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases.
