Researchers have resolved the crystal structure of the activated kappa opioid receptor (KOR) bound to a morphine derivative. They used these findings to create a drug that activates only that receptor, a key step in creating pain medications that avoid some of the negative side effects associated with opioids. Their research was published yesterday in the journal Cell.
The University of North Carolina School of Medicine researchers were seeking to limit off target binding of opioids to unintended receptors, which can cause a wide range of undesired side effects including nausea, numbness, constipation, anxiety, dependency, hallucinations and in extreme cases death caused by respiratory depression. Detailed knowledge of the bound receptor’s structure had previously been unobtainable as imaging with x-ray crystallography is challenging due to the small size and delicacy of opioid receptors and the fact that they do not stay still when bound to a ligand.
To overcome this challenge, the team used Lipidic Cubic Phase crystallization, a technique in which receptor molecules are suspended in specially designed water-lipid mixtures and the water is then slowly removed. To keep the molecules sitting still, the researchers used a variety of experimental tricks, such as the use of an antibody to “prop up” the captor in its active state bound to MP1104, a derivative of morphine.
After obtaining the crystal structure, collaborators at the University of Southern California used computer models of ligands to see which would bind tightly only to the KOR receptor. This information was used to synthesize a new compound that was lab tested for its selectivity to the KOR receptor.
"Now we have a much better understanding of the direction we have to explore in order to create a selective drug to activate only kappa opioid receptors," said corresponding author Daniel Wacker, PhD.
Image: This is an illustration of the active state kappa opioid receptor bound to a morphine derivative (purple). Image courtesy of Tao Che and Daniel Wacker, Roth Lab, UNC School of Medicine.