GWPharmaceuticals is a UK company researching and developing Cannabinoid based medications
Despite the medicinal and recreational use of Cannabis for centuries, the identity of its main psychotropic constituent remained unknown until 1964 when Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute of Science in Rehovot, Israel, isolated and synthesised tetrahydrocannabinol (THC). It was subsequently established that this compound is responsible for the psychotropic effects of the plant, one early hypothesis being that since THC is so hydrophobic it induces these effects by interacting with cell membrane lipids. However as more was learnt about the pharmacology of THC and of synthetic cannabinoids such as CP55940 that induce THC-like effects it became increasingly likely that these effects must be mediated by a distinct family of receptors.
The discovery of cannabinoid receptors….
It was not until 1988 during experiments using radiolabelled CP55940 that the first of these receptors was actually identified. Aptly named cannabinoid receptor type 1 (CB1) it was located at the synapses of the central nervous system and importantly, the peripheral terminals of sensory neurones. CB1 receptors are thought to be the most widely expressed G protein-coupled receptors in the brain but are also found in peripheral tissues including peripheral nerves and non-neuronal tissues such as muscle, liver and fat. A few years later a second receptor (CB2) was identified through homology cloning. This is predominantly expressed in the cells of the immune system.
A receptor requires a ligand…
The discovery of cannabinoid receptors prompted the hypothesis that the body must produce one or more endogenous ligands (naturally occurring molecules) that bind to the receptor. The first such endogenous compound was isolated in 1992, just two years after the cloning of the CB1 receptor. This was the endogenous cannabinoid (endocannabinoid) anandamide (AEA) and investigators have shown that it functions as a CB1 receptor partial agonist. A second endocannabinoid, 2-arachidonoyl gylcerol (2-AG), was discovered a couple of years later and in the following decade several other endogenous molecules that can activate CB receptors were identified. Evidence also emerged that the endocannabinoid system is transiently activated under certain stressful conditions to restore homeostasis.
Ligand biosynthesis and degradation…
Once endogenous cannabinoids were identified it was possible to demonstrate that they are removed from their sites of action by cellular uptake processes and to identify the intracellular enzymes responsible for both their production and metabolic degradation. Diacylglycerol lipase (DAGL) is a key enzyme in the biosynthesis of the 2-AG whereas N-arachidonoylphosphatidylethanolamine-phospholipase D plays an integral role in the production of AEA. Both AEA and 2-AG are inactivated via ester bond hydrolysis and the primary enzymes responsible for these reactions are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) respectively. Endocannabinoid ligands are synthesized on demand rather than stored.
Manipulation of the endocannabinoid system…
There is now good evidence that the endocannabinoid system can be activated not only with compounds that directly target cannabinoid CB1 and/or CB2 receptors but also with inhibitors of endocannabinoid cellular uptake or of the intracellular metabolism of endocannabinoids by FAAH or MAGL. This has prompted a search for phytocannabinoids that can augment endocannabinoid levels by inhibiting these processes or indeed by activating biosynthetic enzymes such as DAGL in a manner that would enhance the protective role that increased endocannabinoid release plays in certain disorders.
Other endocannabinoid targets…
Interestingly, in some scenarios phytocannabinoids, synthetic cannabinoids and endocannabinoids are still able to induce certain effects even when the cannabinoid receptors have been blocked with an antagonist; evidence for the existence of non-CB receptor targets for these molecules. Further studies have demonstrated that these targets include transient receptor potential (TRP) channels such as TRPV1 and TRPM8, the peroxisome proliferator activated receptors (PPAR) alpha and gamma, G protein-coupled orphan receptors such as GRP55, certain ion channels (e.g. calcium channels), transmitter-gated ion channels (e.g. glycine receptors) and finally established non-cannabinoid G protein-coupled receptors(e.g. acetylcholine muscarinic receptors). We are now exploring the potential of phytocannabinoids to interact with targets other than CB1 or CB2 receptors in the search for therapeutically interesting pharmacology.
Originally published on gwpharm.com
contributing authors: Prof Roger Pertwee & Prof Vincenzo Di Marzo