Cannabinoid receptor structure revealed

By: Francisco J. Rojas, Ph.D.

 Marijuana, the cannabis plant, is a psychoactive (mind-altering) drug that contains compounds called cannabinoids. The plant’s primary drug effects come from the chemical delta-9-tetrahydrocannabinol, or THC. Individual cannabinoid chemicals may be isolated and purified from the marijuana plant or synthesized in the laboratory, or they may be naturally occurring (endogenous) cannabinoids found in the body.

There is a growing body of research suggesting the potential therapeutic value of cannabinoids in numerous health conditions including pain, nausea, epilepsy, obesity, wasting disease, addiction, autoimmune disorders, and other conditions. However, some cannabinoids can cause side effects, such as dizziness, hallucinations, and paranoia. Some synthetic cannabinoids, such as K2 or Spice, can produce severe and even deadly reactions.

Cannabinoids exert their primary effects in the brain by binding the human cannabinoid CB1 receptor. Determining the detailed 3-D structure of this receptor is important for potential drug development, as it provides key details about how the receptor and drugs might interact. Last October an international group of scientists published an article in the journal Cell reporting the structure of the CB1 receptor. Their work was funded in part by NIH’s National Institute on Drug Abuse (NIDA).

The scientists synthesized AM6538, a THC-related chemical they designed to help crystallize the CB1 receptor. AM6538 inactivated and slightly modified the CB1 receptor to optimize it for crystallization. They then computed the 3-D structure of the CB1 receptor-AM6538 complex using X-ray crystallography, in which the angles and intensities of X-rays that bounce off a crystal structure are used to determine molecular shape.

The crystal structure revealed that the CB1 receptor has a complex binding pocket with multiple subpockets. Based on prior observations, the scientists were able to predict how other cannabinoids, including THC, would fit into the receptor and how different cannabinoids may interact with the receptor. The findings provide a model to investigate how long each cannabinoids might bind to the CB1 receptor and how each cannabinoid would exert different structural modifications to the receptor.

The interest in the possible therapeutic uses of marijuana is considerable. With Americans across the country consuming marijuana and its constituent compounds for health related conditions, there is a pressing need for well-controlled studies related to their health effects and potential risks, and for more basic research on the biochemical properties of cannabinoids and the physiological systems they affect. The present study on the structure of the CB1 receptor and mechanisms by which different cannabinoids can cause somewhat different effects, will surely help the progress of therapeutic development and clinical trials.