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A new route to fast-acting antidepressants

Chemists design a pathway to ketamine analogs that could open the door to better drug treatments

by Tien Nguyen
September 25, 2017 | A version of this story appeared in Volume 95, Issue 38

Ketamine is a drug that has been administered as an anesthetic for more than 50 years. A decade ago, scientists found that a small dose of ketamine can also serve as a fast-acting antidepressant. Then last year, researchers discovered that ketamine’s antidepressant activity comes from a metabolite, (2R,6R)-hydroxynorketamine (HNK), which lacks ketamine’s psychological side effects that increase its risk of being abused. In yet another ketamine development, a team led by E. J. Corey of Harvard University has now developed an enantioselective synthesis of HNK and related analogs that could help scientists determine the compound’s specific biological target and lead to new antidepressants (Org. Lett. 2017, DOI: 10.1021/acs.orglett.7b02498). The nine-step HNK synthesis contains two novel features. In one step, the team used a mechanistic model of the classic Jacobsen epoxidation reaction to design a modified manganese salen catalyst that enables the epoxidation of an intermediate. In another step, the researchers used aluminum- or titanium-based azide reagents to open the benzylic oxygen position of the epoxide with retention of stereochemical configuration instead of the typical inversion. HNK could be a promising drug candidate, Corey says, because as a ketamine metabolite it has already been encountered by thousands of people.


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