Novel approaches and current challenges with targeting the endocannabinoid system

Abstract

Introduction: The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome. Ligands targeting the canonical cannabinoid receptors, CB₁ and CB₂, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ⁹-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis or seizures in children epilepsy amongst others.

Areas covered: Challenges in the pharmacology of cannabinoids arise from its pharmacokinetics, off-target effects, and psychoactive effects. In this context, the current review outlines the novel molecular approaches emerging in the field discussing their clinical potential.

Expert opinion: Even if orthosteric CB₁ and CB₂ ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.

Keywords: Cannabinoid; allosteric; bias; mitochondrial; multitarget; off-target; peripheral.

Figure 1.

Structure of endocannabinoids AEA and 2-AG, phytocannabinoids Δ⁹-THC and CBD; and synthetic derivatives WIN55,212-2, ORG27569, PNR-4-20 and AMB-FUBINACA.

Figure 2.

Structure of allosteric cannabinoids: ORG27759, ORG29647, GAT211, ZCZ011, PSNCBAM-1, lipoxin A4, pregnenolone, RTI-371, DHGA, trans-β-caryophyllene and structure of the agonist CB1/CB2 CP55,940.

Figure 3.

Structure of pheripheral cannabinoids: AM6545, TM38837, PrNMI, TXX522, LEI-101, DBPR211.

Figure 4.

Structure of multitarget cannabinoids: CB-quinones HU-311 [71], VCE-004.8 and VCE-003.2 [67,68] and chromenopyrazolediones 4 and 10 [69,70]; indazolylketones 5 and 6 [75]; diarylpyrazole derivative 4 [76]; 1,2-dihydro-2-oxo-pyridine-3-carboxamide B1 [77] and CB-opioid bivalent ligands 11 and 19 [86]. Numbers that have been attributed to the structures refer to the corresponding number in original articles.

Figure 5.

Structure of endocannabinoids virodhamine, noladin ether, oleylethanolamide and palmitoylethanolamide; putativee endogenous ligands for GPR55 and GPR18 LPI and NAGly; and synthetic cannabinoids HU210, JWH133, O-1602, Abn-CBD, SR141716A and SR144528.

Figure 6.

Summary of potential approaches to target the ECS. A) Modulation at CB1 and CB2 receptors (G-prot refers to G protein signaling and β-arr to β-arrestin1 or 2 pathways). B) Other targets of cannabinoids.