In the United States, more than 90 people die of overdoses from prescription and illegal opioids every day. The essence of this problem is that opioid drugs like oxycodone, fentanyl, morphine, and heroin, which many people rely on to manage unbearable pain, also have chemical properties that make users feel good, which leads to abuse and addiction. This, in turn, happens because opioids are imprecise, activating not only the receptors on human cells that mitigate pain but also those that trigger addiction.
Fortunately, scientists have woken up to the problem: On Thursday, an international team announced a breakthrough step toward creating new kinds of opioid drugs that relieve pain without any of the side effects.
In a paper published Thursday in the journal Cell, the team reports that they’ve used 3D imaging of opioid receptors to develop a compound that bind to the cell’s pain-mitigating receptor — the kappa-opioid receptor — without binding to the receptors that induce the drug’s feel-good, addictive effects. If they can perfect this, they can theoretically create a new class of opioid drugs that treat pain without exacerbating the opioid crisis.
“As we show in the paper we were able to use the structure to design new drug-like molecules (e.g. candidate medications) with the properties we were expecting,” Bryan Roth, Ph.D., professor of pharmacology at the University of North Carolina and one of the paper’s authors, tells Inverse.
“Going forward, my lab and others will use the structure to help create safer and more effective pain medications.”
Scientists had already known that when the kappa-opioid receptor is bound by an opioid drug, it becomes active, sending signals to the brain to shift its perception of pain. In the study, Roth and his team obtained 3D images of a kappa-opioid receptor in its activated state, and then they used that information to synthesize a drug-like chemical that only activates this receptor — and not any of the other receptors that cause unwanted side effects.
Imaging a receptor in an active state is particularly challenging because it can switch back and forth between active and inactive. To solve this problem, the researchers came up with a unique solution: They stabilized the receptor in its active state with an antibody and a drug-like compound.
While the research is still in its extremely early stages, and the researchers are a way off from bringing new medications onto the market, this paper represents an important development in the efforts to figure out how to get chemicals to bind only to k-opioid receptors and not to others.
“This is an elegant study on the 3-dimensional active-state structure of the kappa opioid receptor,” Christoph Stein, Ph.D., professor of anesthesiology at the Free University of Berlin, tells Inverse. Stein was not involved in this study, but he has also worked on developing non-addictive opioids. He says this paper represents an especially significant advancement in the field because scientists haven’t been able to obtain the structures of these receptors in an active state before now.
That being said, Stein says the study is limited in that it was not conducted in humans or animals, and the receptor the researchers identified was engineered, so it remains to be seen whether a natural receptor would behave the same way. Furthermore, he notes that drug developers are already trying to make opioids that are biased toward kappa-opioid receptors, and these have not yet led to drugs that aren’t addictive.
Still, the team is hopeful that their work will bear results in the future.
“We expect these results to translate into novel drugs with improved selectivity for [kappa-opioid receptors], as most current opioid medications (such as OxyContin or Vicodin) activate all three opioid receptors, which is the reason for some of their side effects,” Daniel Wacker, Ph.D., a research associate in Roth’s lab and one of the paper’s authors, tells Inverse.
“We also show how chemists could modify current medications to target specific downstream signaling of [kappa-opioid receptors], which would further reduce their side effects.”
Wacker points out that kappa-opioid receptors have been a neglected topic in drug research, which he and his colleagues hope to bring into focus.
“[It] has been a neglected target for the design of not only improved pain medication, but also for drugs that might help combat opioid dependence in current addicts,” he says.
Abstract: The k-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective k-opioid receptor therapeutics.