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Biological Chemistry

Inhibiting endocannabinoid reuptake relieves anxiety in mice

First selective reuptake inhibitors suggest new drug target for regulating endocannabinoid signaling

by Michael Torrice
June 12, 2017 | APPEARED IN VOLUME 95, ISSUE 24

Some antidepressants, such as fluoxetine (Prozac), work by preventing neurons from vacuuming up the neurotransmitter serotonin from the gaps between brain cells—a process called reuptake. By doing so, the drugs increase levels of serotonin in the brain and thus elevate mood.

An international team of researchers reports a small molecule that can do something similar for endocannabinoids, a family of greasy signaling molecules that our bodies produce to regulate myriad functions, including appetite, mood, and inflammation (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1704065114). The active ingredient in marijuana, tetrahydrocannabinol (THC), turns on the same receptors targeted by endocannabinoids.

The work points to a possible new approach to regulating endocannabinoid signaling through small-molecule drugs, says Jürg Gertsch of the University of Bern, who led the team.

Other endocannabinoid reuptake inhibitors exist, but they have had a downside: They shut down enzymes responsible for degrading endocannabinoids and other lipids (see page 5), so inhibiting the proteins affects more than just the endocannabinoid system, Gertsch says.

To avoid targeting these enzymes, Gertsch and colleagues screened a library of 634 compounds based on an endocannabinoid-like molecule from the plant Echinacea purpurea that lacks features common to lipids synthesized by our bodies. The winner, WOBE437, potently blocked endocannabinoid reuptake but did not inhibit the degradation enzymes. In mice, WOBE437 increased endocannabinoid levels and had anti-inflammatory and antianxiety effects.

The scientists want to design a probe based on WOBE437 to identify the protein transporters involved in reuptake.

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