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?”

To this end, the researchers will study and characterize the enzymes involved in endocannabinoid biosynthesis on a fundamental and integrated level ranging from molecule to whole organism. Using chemical biology and medicinal chemistry, new compounds will be designed, synthesized and optimized as molecular tools to study and modulate the activity of the biosynthetic enzymes in both in vitro and in vivo models. Metabolomics, systems pharmacology and novel techniques such as organ-on-a-chip will be used to predict and quantify PK-PD relationships, that is, how these molecular probes or drug candidates are taken up and distributed in the body, and how they influence pathways and modify a system’s biological responses.

Finally, innovative behavioural models will be set up to characterize the physiological role of the distinct endocannabinoids in a whole animal model, the zebrafish embryo. This unique integration of disciplines is expected to deliver a more complete understanding of the endocannabinoid system. In addition, it is anticipated that novel compounds that specifically modulate the biosynthetic proteins for anandamide and 2-AG may provide important leads for drug discovery that do not possess the adverse effects associated with general CB1 receptor antagonists.

Photo credits: Tohru Murakami

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).