High-resolution snapshot of ketamine-receptor handshake may point to better antidepressants

Ketamine, a decades-old anesthetic drug, holds much promise as a new antidepressant. It acts more quickly than traditional antidepressants—on the order of hours rather than weeks—and helps people for whom other drugs provide no relief. But ketamine can also cause hallucinations and has the potential for abuse.

Although ketamine’s mechanism of action is still unknown, scientists are seeking similar compounds that treat depression without the anesthetic’s downsides. In a step that could help researchers design such molecules, a team has solved the structure of ketamine bound to a key brain receptor called the NMDA receptor (Nature 2021, DOI: 10.1038/s41586-021-03769-9). Scientists think that ketamine may exert its therapeutic effect through blocking this receptor.

“Our work provides the first structural and functional insights of ketamine inhibition on human NMDA receptors,” Shujia Zhu, a neuroscientist at the Chinese Academy of Sciences in Shanghai who coled the work, says in an email. “Based on the structures, we now know which parts [of ketamine] could be modified and which parts could not” in efforts to develop ketamine-like molecules that don’t have as many side effects.

The researchers incubated one ketamine enantiomer, (S)-ketamine, with two different truncated forms of the NDMA receptor, along with two molecules—glycine and glutamate—which are needed to turn on the receptor. They then used cryo-electron microscopy to snap high-resolution structures of the ketamine molecules bound to the receptors, finding that the drug binds to a region of the protein that spans the lipid bilayer of the cell membrane.

The team also identified two amino acids in the receptor that are crucial for binding with (S)-ketamine. They then used computer modeling to determine how (R)-ketamine sits in the binding site, and identified an additional amino acid in the receptor that appears to be more strongly involved in binding (R)-ketamine than (S)-ketamine.

(S)-ketamine was approved by the US Food and Drug Administration for treatment-resistant depression in 2019. But Todd Gould, a pharmacologist at the University of Maryland School of Medicine who was not involved in the new study, says that it’s not yet clear whether ketamine exerts its antidepressant effect through the NMDA receptor. Animal studies from his lab and others’ show that a metabolite of ketamine called hydroxynorketamine rather than ketamine itself may be responsible for its therapeutic effect, and that hydroxynorketamine doesn’t inhibit the NMDA receptor. That work also suggests that (R)-ketamine is at least as potent an antidepressant as (S)-ketamine and that it also may work through a different receptor.

Hydroxynorketamine and (R)-ketamine are currently in clinical trials, and if they prove to be effective antidepressants, Gould says, “then we will probably be designing drugs that don’t target the NMDA receptor.” But it’s possible that ketamine’s side effects are caused by binding this receptor. So the structural insights from the new study could help develop drugs “that engage ketamine’s therapeutic target but don’t bind the NMDA receptor and therefore don’t elicit those NMDA receptor inhibition-mediated side effects.”