A Guide to Targeting the Endocannabinoid System in Drug Design

Abstract

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands' synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

Keywords: CB1; CB2; ECS; FAAH; MAGL; endocannabinoid system; molecular target.

Figure 1

(A) physiological processes and functions that the endocannabinoid system (ECS) takes part in. In this figure, we gathered probably the most crucial ones in terms of potential therapeutic applications, described in detail in this review; (B) components of the ECS; (C) simplified biochemical pathways of the two main endocannabinoids: 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, also called anandamide (AEA). Blue shapes depict enzymes associated mainly with 2-AG, pink ones—with AEA. Green arrows indicate activation of specific receptors by the endocannabinoids. Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABHD6/12, $\alpha$/$\beta$ hydrolase domain 6 or 12; AEA, N-arachidonoylethanolamine (anandamide); AMT, anandamide membrane transporter; CB1/2, cannabinoid receptor type 1 or 2; COX-2, cyclooxygenase 2; DAG, diacylglycerol; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; FABPs, fatty-acid-binding proteins; GPR18/55/119, G protein-coupled receptor 18 or 55 or 119; HSP70s, 70 kilodalton heat shock proteins; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine acid amidase; NAPE, N-acylphosphatidylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-hydrolyzing phospholipase D; OEA, oleoylethanolamine; PEA, palmitoylethanolamide; PPAR$\gamma$, peroxisome proliferator-activated receptor $\gamma$; TRPV1, transient receptor potential vanilloid type 1 channel.

Figure 2

Simplified presentation of endocannabinoid signaling in the synaptic cleft. 2-AG is synthesized by DAGL in the postsynaptic neuron. After being excreted to the cleft, 2-AG activates presynaptic CB1. Finally, it is degraded by either MAGL in the postsynaptic neuron or by one of the ABHD’s in the presynaptic one. MAGL is colocalized with CB1. ABHD6 regulates AMPA. This is probably important for CB1-independent anti-seizure activity of ABHD6 inhibitors [92,95]. AEA is synthesized by NAPE-PLD. AEA may activate both CB1 and TRPV1, although the latter case is more complex. AEA may act on postsynaptic and presynaptic TRPV1. FABP, HSP70s, and probably AMT take part in AEA reuptake. Blocking this transport may be a valid therapeutic strategy, as it increases AEA extracellular levels, and thus leads to proportionally stronger activation of presynaptic TRPV1 than normal. FAAH inhibition, on the other hand, leads eventually to activation of TRPV1 in both synaptic neurons [93,94]. Green arrows indicate activation of receptors. Bold black arrows show main paths of 2-AG and AEA. Thin black arrows depict colocalization of CB1 and MAGL, and regulation of AMPA by ABHD6. Proteins are colored depending on their functions: enzymes associated mainly with 2-AG (blue), enzymes associated mainly with AEA (pink), eCB reuptake proteins (gray).

Figure 3

A schematic presentation of ECS components targeted in cancer. The figure shows typical and new directions of ECS modulation in neoplasm diseases. Well-investigated directions include the activation of CBRs or TRPV1, suppression of GPR55 signaling as well as the inhibition of FAAH and MAGL. Promising targets may be another cannabinoid degrading enzyme, NAAA [264] as well as CB2 heteromers, such as CB2-HER2 and CB2-CXCR4, as activation of CB2 inhibits HER2 and CXCR4 signaling, respectively [265,266]. Green arrows indicate protein activation, red arrows—inhibition. Black arrows with red lines show HER2 or CXCR4 inhibition by CB2 activation in respective heterodimers.