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May 26, 2016
 |  BC Innovations  |  Targets & Mechanisms

Dissociating ketamine

An NMDA receptor-independent ketamine metabolite might bypass the drug's side effects

For decades, researchers have struggled with the conundrum of how to exploit the antidepressant effects of ketamine without incurring its psychedelic effects. Now, a group from NIH and the University of Maryland has shown that one of the drug's metabolites - (2R,6R)-hydroxynorketamine (HNK) - is responsible for the former but not the latter, and challenged the dogma that the drug works by blocking NMDA receptors. While at least one company invested in that hypothesis is sticking with it, others are lining up to license the metabolite.

The team, led by Todd Gould, an associate professor in the departments of psychiatry and anatomy, neurobiology and pharmacology at the University of Maryland, plans to test the metabolite in the clinic within a year.

"What we've shown is that ketamine's antidepressant actions are not through ketamine itself but via a metabolite, and that metabolite does not inhibit NMDA receptors or have the side effects of ketamine," Gould told BioCentury.

Ketamine, first developed as an anesthetic, has demonstrated rapid antidepressant action in clinical trials of treatment-resistant patients. It has long been viewed as a promising alternative to serotonin-boosting antidepressants, which take weeks to months to work and fail in at least a third of patients.

But the compound has severe dissociative effects, often leading to hallucinations, and abuse liability.

While ketamine has several CNS targets, its anesthetic effects are mediated via blockade of the NMDA receptor, and that mechanism is proposed to underlie its activity in depression as well.

Researchers in industry and academia have looked for ways to antagonize NMDA receptors with other compounds that have fewer liabilities, and at least eight companies are targeting the receptor, either alone or in combination with other receptors, to treat the disorder (see Figure: Ketamine mimics).

But Carlos Zarate, chief of the experimental therapeutics and pathophysiology branch at NIH's National Institute of Mental Health (NIMH), who was one of the authors on the new study, told BioCentury no one has directly proved the NMDA hypothesis. "Everybody assumed that the mechanism of ketamine's antidepressant effect was NMDA antagonism, but that mechanism had only really been shown for it as an anesthetic agent," he said.

Derek Lowe, a medicinal chemist and author of a widely read blog on drug research, told BioCentury that while ketamine inhibits NMDA receptors, its effects at other receptors should not be ignored. "We don't know what level of binding is sufficient to set off different targets" of the drug, he said.

Moreover, Lowe said NMDA receptor blockade almost certainly contributes to the drug's undesirable side effects since other NMDA antagonists that have been investigated for depression also cause psychological disturbance.

"A lot of people have taken a crack at the straight NMDA approach to depression but no one's gotten anything through the clinic. At this point you might want to say it's time to try a new approach," Lowe said.

Zarate said his group focused on the metabolites of...

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