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
• peripheral
• mitochondrial
• multitarget
• off-target

Article highlights

• Novel strategies for targeting the endocannabinoid system include allosterism and bias signalling.

• Multi-target approaches could be promising strategies for the treatment of endocannabinoid system-related disorders.

• Full characterization of signalling pathways needs to be accomplished for drug candidates targeting the ECS.

• High-resolution structures of cannabinoid receptors will help in guiding future drug design.

• The authors believe that phytocannabinoids are at the forefront of future clinical research.

This box summarizes the key points contained in the article.

Acknowledgments

The authors thank Dow H. Hurst for his English review.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

N Jagerovic is supported by the Ministry of Science, Innovation, and Universities, Spain (MCIU)/FEDER grant RTI2018-095544-B-I00, the Spanish National Research Council (CSIC) grant PIE-201580E033 and National Institutes of Health grant R01 DA0455698-01. Meanwhile, P Morales is supported by the Comunidad de Madrid (CM) programme ‘Attraccion de Talentos’ number 2018-T28MD-10819.