Study identifies compounds that may improve treatment of opioid addiction

Good news! Can we finally better help people to rid themselves of their addiction! 

About two hundred million small molecules were initially evaluated! Very impressive! More to come!

"Since the 1960s, the hallucinogenic drug ibogaine has piqued interest as a potential treatment for opioid addiction, fueled by limited experimental evidence and anecdotal claims by those who claim they no longer felt a craving for opioids after taking ibogaine. But the drug comes with risks, including heart disorders and death. In a new study, ... identified two compounds that, in experiments with mice, were shown to be more biologically targeted than ibogaine but, like the hallucinogen, ameliorated symptoms of depression, anxiety, and opioid withdrawal. ..."

From the highlights and abstract:

"Highlights

• Large-library docking finds conformationally and target-selective SERT inhibitors

• Cryo-EM supports the computationally predicted structure

• The inhibitors are anti-depressant-like and alleviate opioid withdrawal in mice

• Targeting of transporters for structure-based ligand discovery

Summary

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine’s promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects."

Study identifies compounds that may improve treatment of opioid addiction | YaleNews Searching for compounds with the therapeutic effects of ibogaine but not its toxicity, researchers found two that eased depression and opioid withdrawal.

Structure-based discovery of conformationally selective inhibitors of the serotonin transporter (no public access)

Graphical abstract