The Faculty of Science of Leiden University has started a multidisciplinary research programme to investigate the role of the human body’s own marijuana. Researchers from Chemistry, Biology and Pharmaceutical Sciences work together to unravel and control the function of endocannabinoids in the brain during health and disease.

Faculty of Science Profile Programme: “Endocannabinoids”

Recently, the Faculty of Science at the Leiden University has started a program to investigate the role of proteins responsible for the biosynthesis of the Endocannabinoids. In this multi-disciplinary project researchers from the Leiden Institute of Chemistry (LIC), Leiden Academic Center for Drug Research (LACDR) and Institute for Biology Leiden (IBL) will collaborate to address the fundamental questions: “Why does the cannabinoid CB1 receptor use two endogenous ligands in the central nervous system?” and “How does this affect its molecular interaction with the stress pathway?”

Endocannabinoids in health and disease

Endocannabinoids are signalling molecules formed by the human brain; they activate a protein called the cannabinoid CB1 receptor. This protein can be hijacked by the main component of marijuana (Δ9-THC) and is responsible for a person becoming “high” or “stoned”, and is also linked to binge eating (i.e. having the munchies). Continuous stimulation of the CB1 receptor by the endocannabinoids is associated with nicotine addiction, obesity and metabolic syndrome; these are all major risk factors for illness and death in Europe.

Medicinal marijuana

Marijuana is the most widely used illegal drug throughout the world and has aroused great controversies. Nowadays you can buy marijuana (the so-called ‘MediWiet’) on prescription in the drug store. It may help to relieve the symptoms of patients suffering from multiple sclerosis, restore appetite or suppress nausea in cancer patients treated with chemotherapy. Marijuana (bangh, hashish) is an extract from the plant Cannabis Sativa that contains at least 400 chemical components of which 60 belong to the class of cannabinoids.

Endocannabinoids: the body’s own marijuana

The presence of cannabinoid receptors in mammals suggested the existence of endogenous molecules in the brain, which bind and activate these proteins. In 1992, almost 30 years after his discovery of THC, professor Mechoulam isolated the first endogenous compound for these receptors from porcine brain. This component proved to be a lipid: N-arachidonoylethanolamine. The compound was called anandamide ("ananda" is Sanskrit for internal bliss). 

Partners

In a multidisciplinary research line, in which organic and medicinal chemistry are combined with molecular biology and chemical biology, we aim to a) develop assays to determine the activity of proteins, and b) to design, synthesize and characterize small molecules that act as chemical tools to visualize and control protein activity. We use computational chemistry together with activity-based probes for compound profiling and optimization. In (inter)national collaborations with biologists and pharmacologists we test our molecules in preclinical models of disease. We aim to develop molecular tools to visualize and control the biosynthetic enzymes and the receptors of the endocannabinoids.

Our group carries out research on vertebrate developmental biology. We not only study fundamental questions of development and evolution, but we also use the zebrafish model system to study the effects of compounds including cannabinoids. In addition, we are interested in stress-related pathways, in particular the regulation of the secretion of the glucocorticoid hormone cortisol.

Within the Profile Programme we use zebrafish embryos and larvae to screen compounds that modulate (endo-)cannabinoid levels and synthetic (ant)agonists, for their  effects on behaviour. We will also study the development of various components of the endocannabinoid system in terms of gene expression. Mutant and transgenic fish will be used to probe the function of the endocannabinoid system. And finally, we will examine the relationship between the endocannabinoid system and the system that regulates the secretion of cortisol after stress.

Current research focusses on the development and use of a metabolomics-based study of disease pathology and physiology, and to discover biomarkers for the early diagnosis of diseases and the prediction of pharmacological treatments. This knowledge is used to better understand and optimize current pharmacological treatments, or to develop novel pharmacological treatments. For this, Thomas has developed a wide range of mass-spectrometry based metabolomics platforms suitable for clinical and preclinical samples. Together, Piet Hein and Thomas are developing a systems pharmacology approach to (i) identify novel drug targets, (ii) assess the target engagement of existing or novel drug candidates, and (iii) translate in-vitro and in-vivo findings via quantitative modelling to clinical use. In (inter)national collaborations with academic and industrial partners they are involved in various systems biology projects aiming to develop novel treatments of multifactorial diseases. Both have been involved in studying the effects on drugs on the endocannabinoid system.

The group of Prof. Ad IJzerman & Dr. Laura Heitman aims to understand ligand-receptor interactions and thereby drug action. The group wants to use that understanding for a more rational approach of drug design and thereby improve drug candidates. For this, they pursue a ‘medicinal chemistry’ approach, in which synthetic chemistry, bio- and cheminformatics, biochemistry/molecular biology and molecular pharmacology are combined. The group is interested in so-called novel receptor concepts that might improve drug action, three of which are ‘allosteric modulation’, ‘inverse agonism’, and ‘drug-target kinetics’. These themes are applied on G protein-coupled receptors (GPCRs).

Within the Profile Programme the group works on two of these GPCRs, namely the cannabinoid receptor 1 and 2. Here the research is evolved around the concept of drug-target kinetics for two reasons: 1) to identify kinetic parameters, such as association rates and target residence times, that support the differentiation of ligands and evaluate to which extent these parameters can be exploited to predict or optimize selectivity and in vivo efficacy of ligands, and 2) to optimize probes’ binding kinetics for activity-based protein profiling (ABPP) to increase the labeling efficiency and reduce off-target labeling.

International collaborations

The partners within the Endocannabinoids research programme collaborate with both international public-private and academic institutions. Click on the map below to find out more about our collaborations.

Grants

Awarded to:
Dr. M. van der Stelt, Dr. L. Heitman
Funding agency:
NWO-CW, ECHO-STIP
Project title:
Novel Target Engagement Biomarkers for Better Drug Candidates
Period:
01-10-2013 to 01-10-2017
Awarded to:
Dr. M. van der Stelt
Funding agency:
NWO-CW, ECHO
Project title:
Novel Chemical Tools for Target Validation in Neuroinflammation
Period:
29-04-2014 to 01-01-2019
Awarded to:
Dr. M. van der Stelt, Dr. L. Heitman, Prof. dr. A. IJzerman
Funding agency:
Roche Postdoc Fellowship Program
Project title:
Establishment of Structure−Kinetics Relation for CB2 Ligands
Period:
01-01-2015 to 01-01-2017
Awarded to:
Prof. M.K. Richardson
Funding agency:
Netherlands government, Smart Mix consortium grant
Project title:
A New Generation of Biomedical Research Tools
Period:
2007 to 2015

Awards granted to Endocannabinoid research

2005
ICAM Award for Young Researchers for major contributions to Cannabinoid Research
International Association for Cannabis as Medicine
Leiden, the Netherlands
2003
Young Scientist Award
European Society for Neurochemistry
Warsaw, Poland

People involved within the research

PhD students working within the Endocannabinoids research profile programme

Vasu Kantae (LACDR)
Floris Luchtenburg (IBL)
Elliot Mock (LIC)

PhD students and post-docs involved in Endocannabinoids research

Tom van der Wel
Juan Zhou
Andrea Martella (post-doc)
Marc Baggelaar
Soumya Deep Chatterjee
Hui Deng
Annelot van Esbroeck
Anthe Janssen
Freek Janssen
Eva van Rooden
Marjolein Soethoudt