Targeting CB1 Endocannabinoid Receptor: Specificity is the Key

WRITTEN BY: Amy Loriaux

The human endocannabinoid system (ECS) is one of the body's largest network of neurotransmitters, receptors, and neuromodulators. This system plays a role in a myriad of functions and disorders, from cancer, metabolic and eating disorders, neurodegeneration, locomotion, pain, liver disease, and immunosuppression. The CB1 receptor is the most abundant of the ECS receptors in the central nervous system (CNS) but is expressed at low concentrations in other organs, such as the spleen, lungs, etc. These receptors are primarily inhibitory, that is, they will attenuate nerve signaling, but their effects depend on where their receptors are located. For instance, there are CB1 receptors on the signaling (i.e. firing) neuron, which means endocannabinoids (ECs) can modulate neurons on both sides of the synapse.

Photo Source: UnSplash.com

The ubiquity of the CB1 receptor in the body and its role in many physiological mechanisms makes it a novel candidate for a therapeutic drug target. Scientists and pharmaceutical companies have been working to target this receptor for a while, but only a few have made it to market due to severe psychological side effects. For example, rimonabant, a CB1 antagonist used for the treatment of obesity, was in Phase III clinical trials before it was shelved due to the development of suicidal thoughts in patients.

So, this would seem that targeting the CB1 receptor is not a great idea. However, new evidence suggests that the CB1 receptor has multiple conformations or molecular arrangments and that they have what are called allosteric binding sites (see video below). Essentially, these are areas of the receptor other than the main binding site, which, if activated, can alter the way the receptor reacts to its specific ligand. Benzodiazepines and barbiturates work this way on the GABA-A receptor. Each of these allosteric sites may be exploited for therapeutic use. Allosteric binding pockets have amino acid sequences that may be more specific for each receptor.

Photo Source: UnSplash.com

Some drug companies are already using this specificity of allosteric binding on the CB1 receptor. The development of these drugs are right now in the nonclinical stage, that is essentially synthesizing compounds in the lab with the ability to target allosteric sites on the CB1 receptor. Many of these compounds are being tested using various in vitro assays to test proof of concept. Patents have been filed. If this technique is really as good as it is predicted to be, we may have a new medication on our hand to treat disorders from opioid addiction to cancer. We will have to wait and see. The video below has a visual aid for understanding allosteric modulators. Note: they refer to enzymes but the same can be said for receptors.