Characterization of ligand bias at the type 1 cannabinoid receptor

The type 1 cannabinoid receptor (CB1) regulates several processes, including pain perception, motor coordination, mood, reward, and appetite. CB1 is considered a major drug target for the treatment of pain, Huntington and Parkinson diseases, addiction, and obesity. Drugs (aka ligands) are usually thought of as compounds that selectively interact with a target in the body - for example, a receptor - to cause a specific effect. However, some drugs cause multiple effects because their receptors can act through multiple pathways within a cell. For example, delta9-tetrahydrocannabinol (THC), the major active drug in marijuana, may reduce pain by activating one set of proteins associated with CB1 and stimulate appetite by activating another set of proteins associated with CB1. A drug can be described as biased if it favours the activation of one set of proteins over another at the same receptor. This is known as ligand bias. A biased cannabinoid drug could selectively reduce pain without causing the other effects associated with CB1 activation, such as appetite stimulation, dizziness, and feelings of intoxication. The objective of my research project is to characterize CB1 ligand bias in order to develop safe and effective CB1-targetted drugs. CB1 ligand bias will be studied by testing a series of CB1-specific probe compounds in cell culture and animal behaviour experiments. These probe compounds permanently attach to specific parts of CB1 that may be important for ligand bias. Experiments with these probe compounds in cell culture will demonstrate which parts of CB1 are responsible for the differing effect cannabinoid drugs are known to have. Subsequent behavioural experiments in animals will then be used to demonstrate how the bias of a probe compound at the molecular level is shown in a living animal. From this research, biased ligands will be developed as effective CB1-targeted therapeutics.