Like all drugs, cannabis – or, more specifically, the active ingredient tetrahydrocannabinol (THC) – binds to receptors in the brain in order to produce its effects. While scientists have known about THC since the 1960s, it took them until this month to produce the first-ever 3D image of the receptor that it locks onto, revealing its structure and binding sites.
Cannabinoids like THC attach to the brain’s cannabinoid receptors, which also attract the body’s own naturally occurring cannabinoids – known as endocannabinoids – as well as other synthetic substances that fall into this same category. Of primary concern is cannabinoid receptor 1 (CB1), which is responsible for producing many of the effects normally associated with being stoned.
While this may be straightforward enough, scientists have until now struggled to understand why different cannabinoids produce different effects when they bind to CB1. For example, writing in the journal Cell, the researchers explain that no fatal overdose involving THC has ever been recorded, although several synthetic cannabinoids have proven deadly. On the other hand, some cannabinoids have medicinal properties, and are effective at treating chronic pain, multiple sclerosis, and other conditions.
The structure of the CB1 receptor has finally been revealed. Liu at al / Cell
It is therefore thought that by improving our understanding of how CB1 interacts with various cannabinoids, it may one day be possible to create new drugs with enhanced therapeutic value and no dangerous side-effects.
To achieve this, the study authors first crystalized CB1 receptors using a stabilizing substance called AM6538 that binds to the receptor. They were then able to use a range of imaging and analysis techniques such as mass spectrometry to create a 3D visualization of the receptor, observing how it attaches to AM6538 and illuminating the various other binding sites.
“The crystal structure of CB1 in complex with AM6538 reveals an expansive and complicated binding pocket network consisting of multiple sub-pockets and channels to various regions of the receptor,” write the study authors.
For instance, they reveal that the receptor has a three-armed structure, and that one of these arms in particular can interact with a diverse range of compounds. By designing new drugs that target this arm of the CB1 receptor, it is hoped that researchers may soon be able to develop novel therapeutic cannabinoids.
