24 October 2016

How Marijuana Turns The Brain On

The crystal structure of the human cannabinoid receptor could help explain the unexpectedly complex and occasionally harmful effects of marijuana.

Asian Scientist Newsroom | October 24, 2016 | In the Lab AsianScientist (Oct. 24, 2016) –

An international group of scientists has created an atomic-level image of the receptor activated by tetrahydrocannabinol (THC), the active chemical in marijuana. Details were published in Cell.

As marijuana use becomes more common, it is critical that we understand how it works in the human body, according to Professor Liu Zhi-Jie from Shanghai Tech University in China, who co-led the study with three other researchers.

At the beginning of the study, the team struggled to produce a crystal form—needed to obtain data to recreate the high-resolution structure—of the receptor bound with AM6538, a stabilizing molecule that blocks the receptor’s action. AM6538 has a long half-life, making it potentially useful as a treatment of addiction disorders.

When the scientists finally succeeded in crystallizing the receptor and collecting the data, the structure of the cannabinoid receptor complex revealed an expansive and complicated binding pocket network consisting of multiple sub-pockets and channels to various regions of the receptor.

Cannabinoid receptors are part of a large class of receptors known as G protein-coupled receptors (GPCR), which account for about 40 percent of all prescription pharmaceuticals on the market and play key roles in many physiological functions.

When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.

The new insights into the human cannabinoid receptor 1 will provide an essential tool for understanding why some molecules related to THC have unexpectedly complex and sometimes harmful effects. The findings also have the potential to guide drug design for pain, inflammation, obesity, fibrosis and other indications.

The article can be found at: Hua et al. (2016) Crystal Structure of the Human Cannabinoid Receptor CB1.

——— Source: The Scripps Research Institute; Photo: Pixabay. Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

http://www.cell.com/cell/abstract/S0092-8674(16)31385-X?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286741631385X%3Fshowall%3Dtrue

Highlights

  • AM6538 is presented as a stabilizing, tight binding antagonist of CB1
  • Crystal structure of human CB1 in complex with AM6538 is determined
  • Molecular docking predicts CB1 binding modes of THC and synthetic cannabinoids
  • Resolution of the binding pocket provides path for rational CB1 drug design

Summary

Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.

Basic CMYK

Read more from Asian Scientist Magazine at: http://www.asianscientist.com/2016/10/in-the-lab/tetrahydrocannabinol-human-marijuana-receptor-unveiled/