The endocannabinoid system - current implications for drug development

Abstract

In this review, the state of the art for compounds affecting the endocannabinoid (eCB) system is described with a focus on the treatment of pain. Amongst directly acting CB receptor ligands, clinical experience with ∆⁹ -tetrahydracannabinol and medical cannabis in chronic non-cancer pain indicates that there are differences between the benefits perceived by patients and the at best modest effect seen in meta-analyses of randomized controlled trials. The reason for this difference is not known but may involve differences in the type of patients that are recruited, the study conditions that are chosen and the degree to which biases such as reporting bias are operative. Other directly acting CB receptor ligands such as biased agonists and allosteric receptor modulators have not yet reached the clinic. Amongst indirectly acting compounds targeting the enzymes responsible for the synthesis and catabolism of the eCBs anandamide and 2-arachidonoylglycerol, fatty acid amide hydrolase (FAAH) inhibitors have been investigated clinically but were per se not useful for the treatment of pain, although they may be useful for the treatment of post-traumatic stress disorder and cannabis use disorder. Dual-acting compounds targeting this enzyme and other targets such as cyclooxygenase-2 or transient potential vanilloid receptor 1 may be a way forward for the treatment of pain.

Keywords: anxiety; cannabinoid receptors; endocannabinoid; fatty acid amide hydrolase; pain; ∆9-tetrahydrocannabinol.

Fig. 1

Different conformations of G‐protein‐coupled receptors and their responses. In this simple example (Panel a), the receptor is in three conformations: an inactive and two active conformations that couple to different transduction pathways and responses. These conformations are in equilibrium with each other, and in ‘rest’ conditions, most of the receptor is usually in the inactive form. Agonists have high affinities for the active forms and shift the equilibrium to the right (i.e. the active forms), whereas inverse agonists have high affinities for the inactive form and shift the equilibrium to the left. Neutral antagonists are high‐affinity compounds that bind to all forms with equal affinities and thus do not move the equilibrium, but prevent agonists from doing so. Biased agonists bind with different affinities to the active forms and thus favour one of the active forms [186]. This means that in theory the concentration‐response curves for response A and B are similar for agonists (‘balanced agonists’, Panel b), but different for biased agonists (Panel c). In practice, the curves for balanced agonists are not necessarily the same due to factors such as coupling efficiencies, expression of target response proteins etc, and so the degree of bias is often described relative to a standard compound (see [187] for examples with the CB₁ receptor, where Response A is recruitment of an engineered mini‐Gα_i protein and Response B is recruitment of β‐arrestin2).

Fig. 2

AEA and 2‐AG turnover starting from the appropriate NAPE and diacylglycerol (DAG), respectively. The thick arrows show the canonical pathway, with alternate pathways (reviewed in [80, 81]) for the synthesis and degradation being shown with the thin arrows. Abbreviations (when not given in the text): AA, arachidonic acid; EA, ethanolamide; GE, glyceryl ester. Note that the PG‐EA, PG and PG‐GE species shown is F_2α, but the corresponding D₂ and E₂ species are also formed. Note also that the PG‐GEs rapidly isomerize to form the corresponding PG‐1‐GEs, and this form dominates in PG‐GEs preparations that are commercially available.

Fig. 3

Panel (a) relative rates of hydrolysis of the NAEs PEA, OEA and AEA by FAAH, FAAH‐2 and NAAA. The data for FAAH and FAAH‐2 were taken from Table 2 of Wei et al. [103] who used COS‐7 cells transfected with human FAAH‐1‐pcDNA3 or FAAH‐2‐pFLAG.CMV6 constructs and an assay pH of 9 (the pH optimum for FAAH). The data for NAAA (right axis) were estimated from Fig. 7 of Ueda et al. [104] who used NAAA purified from rat lung enzyme and an assay pH of 5 (in the presence of Triton X‐100) and expressed the activity with AEA and OEA relative to that with PEA as substrate. The error bars (when not too small to be visible in the original study [AEA for NAAA] or when the activity was set to 100% [PEA for NAAA]) represent SD. Panel (b) shows the potency ratio of four inhibitors towards FAAH and FAAH‐2, calculated from [103] and [129]. The higher the number, the greater the selectivity towards FAAH.

Fig. 4

Structures of dual‐action FAAH / COX inhibitors based upon a) ibuprofen and b) flurbiprofen [150, 151, 152, 153].