Scientists Map the Receptor That Makes Weed Work

March 20, 2019 Off By HotelSalesCareers

Add marijuana to humans, and you get some fairly predictable results: euphoria, hunger, introspection, anxiety, and a whole panoply of other effects. Also known as being high. Most of that complicated reaction is thanks to a single cellular structure known as cannabinoid receptor 1. Your body has CB1 receptors lacing the surfaces of cells in the brain, liver, lungs, fat, uterus, and sperm. And whenever your … friend smokes, dabs, or eats an edible, the tetrahydrocannabinol molecules therein bind to these sites, stimulating the cells to release a cornucopia of chemical signals.

For a long time, scientists thought CB1 receptors worked like lock and key with THC and its chemical cousins—one size fits one. However, new research shows that CB1 receptors are actually quite malleable, stretching to fit a wider range of molecules. That could be useful knowledge as researchers try to synthesize chemicals that mimic the desirable effects of cannabis (such as pain relief) without the side effects (such as anxiety, weight gain, addiction, or federal prosecution).

"People have been using cannabis for a variety of therapeutic indications for centuries," says Alexandros Makriyannis, director of Northeastern University's Center for Drug Discovery, and a co-author of this new research, published in Nature. In the 1960s, scientists finally started to figure that out as well. And by the 1980s, Eli Lilly had developed a synthetic THC knockoff called Nabilone. "It was a good quality drug used for nausea from chemotherapy, and also pain," says Makriyannis. But other THC-based synthetics never took off, in part because pharmacologists couldn't eliminate all the unwanted side effects.

Still, cannabinoid receptors are such promising therapeutic targets that some researchers persist. Makriyannis has been at it for decades, and has discovered dozens of compounds that interact with either CB1 or its cousin, CB2. THC, the active ingredient in weed, is just one of those. Your body even makes its own, called endocannabinoids, that are involved with modulating your appetite, mood, memory, and pain. Scientists, including Makriyannis, have synthesized many more. And last year, he made an even more significant discovery: a compound that could turn the CB1 receptor off. An anti-high, if you will.

That discovery gave arise to this latest finding, of CB1's malleability. See, the molecules that switch CB1 on—THC and other cannabinoids—are about 100 times smaller than the receptor they turn on. Curious, Makriyannis and his Northwestern team, along with researchers in China, California, and Florida, set about visualizing the receptor in various states of activation and deactivation using a technique called X-ray crystallography.

If X-ray crystallography sounds familiar, it's probably because it's the same technique Rosalind Franklin used to visualize the structure of DNA in 1952. Most molecules are too small for a typical microscope to see. This method gets around that turning the tiny molecule into a crystal—its structure repeated over and over again in the exact same orientation. X-rays pass through the crystal structure, then collide with a sensor on the other side. The scientists collect that impression from the sensor, really just a bunch of data, and mathematically reconstruct the molecule's shape.

CB1 receptors looks like a bundle of microscopic sausage links. The sausages, seven in all, are spirals of amino acids that weave in and out of a cell's membrane. And they are very flexible. When a cannabinoid goes into the receptor, the sausage links—called helices—coalesce around that receptor's binding site. The big surprise came when Makriyannis' group crystallized CB1 as it was binding to the THC-like molecules meant to switch it on. The crystallography revealed that two of the helices twisted and collapsed to fit around the molecule, shrinking the receptor to less than half its size when it received the off-switch molecule. Never mind the lock and key: CB1 is like a door that opens to the tune of many different secret knocks.

Makriyannis says this is a big breakthrough for his work, and that he'll keep looking for new cannabinoid molecules. "We want to make compounds that will modify the receptor differently, so we can make better drugs," he says. (He and his co-authors will present more of their work at the Chemistry and Pharmacology of Drug Abuse annual symposium from August 9 to 12 at Northeastern University.) His hope is that he can create finely-tuned molecules that will trigger CB1 to send anti-nausea signals to the body, without things like irritability, anxiety, or addiction. You could say he has a higher calling.

Scientists Map the Receptor That Makes Weed Work

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