Say that you smoked marijuana right now. It would do things to your mind and to your body. You could become overly excited and real giggly. You might feel relaxed and introspective. You could become paranoid, and hungry, and drowsy.
Those are some of the effects that tetrahydrocannabinol, the main psychoactive compound in marijuana, might have on you and the trillions of cells within your body. Because of the abilities of compounds in marijuana to stimulate our sensations, some people use cannabis to cope with chronic pain, anxiety, and other health problems.
But tetrahydrocannabinol is just one of the many compounds in a class of molecules known as the cannabinoids, which can also be found within your body even if you don’t use marijuana or products derived from it.
Right now, your body is growing its own crop of cannabinoids to run itself smoothly. It uses the endocannabinoid system, and it is how mood, appetite, and other sensations are regulated.
Alexandros Makriyannis, George D. Behrakis Chair of pharmaceutical biotechnology at Northeastern, says there are many ways to design new molecules in the lab to tweak that endocannabinoid system and control several of the biochemical reactions that lead to anxiety, chronic pain, and other physiological processes.
Makriyannis, also a professor of chemistry and chemical biology, is on a quest to synthesize these molecules. The idea is to use the benefits of cannabinoids like those found in marijuana, while leaving the potential negative effects behind.
“We can produce medications for pain, medications that deal with liver diseases, with sleep—a wide variety of these by making molecules that can turn these switches on or off more precisely,” says Makriyannis, who directs the Center for Drug Discovery at Northeastern.
In a new paper published in Cell, a team of scientists that includes Makriyannis revealed for the first time the complete, three-dimensional structure of the body’s endocannabinoid receptors, the proteins in our cells responsible for the effects of cannabinoids.
The team’s findings present a snapshot that provides a full view of the structure of cannabinoid receptor type two, or CB2, one of the two types of cannabinoid receptors in our cells.
The newly unveiled structures are enabling scientists to account for the effect of cannabinoid molecules such as tetrahydrocannabinol on the body, and will also be used to develop novel therapeutic medications, Makriyannis says.
“You could use this as a basis to develop new molecules, new keys that could modulate the function of this protein,” he says. “We can make them in different flavors, for different conditions.”
All of our cells—within our brain, lungs, kidneys, liver—are coated with two types of proteins that are exclusively receptive to cannabinoid compounds. Makriyannis thinks of these receptor proteins as switches. Cannabinoids, he says, act as special keys that turn those switches on and off in different ways.
“Once you know the structure of this receptor, you can get the mechanism of how it produces different effects when modulated,” Makriyannis says. “If you change that key, you might get a different type of an effect.”
Proteins do most of the heavy lifting inside our cells. They consist of long and complex chains of amino acids that perform essential functions to orchestrate all of the cellular and high-level functions that keep us alive.
To do their jobs, proteins rely on their shape. The structure of antibody proteins, for example, enables them to fight pathogens entering our bodies. And proteins that are misshapen can cause diseases such as Alzheimer’s disease or cystic fibrosis.
Makriyannis focuses on mapping the exact structure of cannabinoid receptors to make new molecules that would fit neatly with their shape to control different functions within the endocannabinoid system.
One of the primary challenges of mapping those structures is the molecular resemblance of the receptors. Although they are remarkably similar, they exert different functions within our bodies.
Cannabinoid receptor type one, or CB1, plays a key role in controlling appetite and mood disorders. CB2 is involved in the immune system, in diseases such as cancer and fibrosis in the liver and kidney.
With the right molecule, these receptors could be switched on and off at will for targeted therapeutic medications, Makriyannis says. And there’s more than one type of key that can move those switches.
“You can make them turn off completely, or partly turn them on—or super turn them on,” he says. “Or you can turn them on in the brain, or turn them on in the liver but not in the brain—you can play a lot, and that’s what we’ve been doing.”
Until recently, researchers did not have a complete picture of the structure of CB2. That made maximizing the therapeutic potential of cannabinoids difficult, as previous efforts to design new drugs yielded treatments that weren’t completely effective and came with potential side effects.
In 2016, Makriyannis’ team mapped the structure of CB1. Having mapped the second receptor in its off configuration in 2019, the team has now completed a roadmap that reveals the different mechanisms in which both types of receptors are activated or deactivated.
That’s helping Makriyannis and other scientists to fine-tune new molecules that will lead to improvements in various therapeutic treatments, he says.
“One of our more advanced compounds is what one might call a neutral cannabinoid 1 antagonist,” Makriyannis says. “We are trying to develop it in humans to deal with diseases of the liver, especially liver cirrhosis and liver fibrosis.”
Makriyannis is also thinking in terms of complex conditions involving long-lasting chronic pain and mental health.
“Another compound that is a CB2 agonist, which turns the CB2 receptor on, can protect people from neuropathic pain,” Makriyannis says. “We’re also developing a pill to be taken before going to sleep, which is one of the most difficult parts of PTSD.”