More than 1 billion people around the world suffer from chronic pain, which can interfere with quality of life, affect a person's ability to work, and cause or exacerbate mental health issues. Currently, the only consistently effective treatments for chronic pain are opioids, which come with severe risks of addiction and fatal overdose.
Researchers at Stanford University and Washington University School of Medicine in St. Louis have designed a new compound to potentially treat chronic pain that targets type 1 cannabinoid (CB1) receptors, which are proteins on the surface of cells throughout the body that bind to cannabinoids - chemical compounds made by the body or found in plants like cannabis. In a paper published March 5 in Nature, the researchers demonstrate that the compound can effectively treat multiple types of pain in mouse models without causing the psychoactive side effects typically associated with the CB1 receptor or causing the mice to build up a tolerance to it.
"We rationally designed compounds with the properties that we wanted," said Alexander Powers, co-first author on the paper, who conducted the work while earning his PhD in chemistry at Stanford. "This molecule shows that we can get a separation between the side effects and the analgesic effects - we can target the CB1 receptor and get the good effects without the bad."
A cryptic pocket
Researchers have been interested in targeting the CB1 receptor - so named because it is a binding site for the tetrahydrocannabinol (THC) molecules in cannabis - to treat chronic pain for decades. Synthetic molecules targeting the CB1 receptor have shown strong pain-relieving properties, but they also tend to cause severe psychoactive side effects and lose their effectiveness over time.
The Stanford researchers started looking for new ways to target the CB1 receptor by running 3D computer simulations of its movements. Like most proteins, CB1 constantly shifts between different shapes, and these structural changes influence which compounds can bind to it and what signals it transmits.
Other groups have identified several structures of the CB1 receptor using experimental methods, but Powers and his colleagues were looking for something new. Through their simulations, they discovered a previously unknown "cryptic pocket" - a binding site that is not present in the experimentally determined structures but opens transiently in simulations.
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Molecules binding to CB1 receptor protein: previous molecule (left) and newly engineered molecule engaging the cryptic pocket (right). | Alexander Powers
