r/DrugNerds • u/Robert_Larsson • Jul 20 '26
AI-derived therapeutic development of a serotonin receptor–targeting drug for the treatment of opioid use disorder (8-fluoro derivative of ibogainalog)
https://pmc.ncbi.nlm.nih.gov/articles/PMC13079983/Significance
The premise of these studies was to develop and validate a therapeutic for opioid use disorder. Using an AI-based platform aimed at polypharmacy-focused drug discovery, two compounds were synthesized and tested, GATC-021 and GATC-1021. We found that GATC-1021, which targets the 5-HT2A and 5-HT6 receptors,, was highly selective in attenuating fentanyl self-administration in male and female rats, with retained effectiveness following repeated dosing. Following GATC-1021 treatment, an increase in the percentage of thin dendritic spines in the hippocampus and changes in gene expression pathways involved in neuroplasticity in the prefrontal cortex were evidenced. Taken together, these findings provide a foundation to support the further clinical development of GATC-1021 as a potential treatment for individuals suffering from opioid use disorder.
Abstract
The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, including fentanyl. Here, we developed a therapeutic drug based on an AI-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. Two top candidate compounds, GATC-021 and GATC-1021, were synthesized and validated with in vitro screening for target specificity. Thereafter, the drug candidates were examined for their effectiveness in modulating opioid reinforcement and intake. GATC-1021 emerged as the most efficacious compound as it significantly decreased fentanyl intake in both male and female rats, without any notable side effects. GATC-1021 was further found to modulate gene expression patterns in addiction-relevant brain regions following fentanyl-induced alterations. These findings validate GATC’s AI-based platform with its polypharmacy-focused drug development approach and further support the clinical potential of GATC-1021 as a promising therapeutic for those suffering from opioid use disorder.
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u/SentientMonoamine Jul 20 '26
Very interesting. I'm not an SAR/Drug discovery guy, but I am working with a dual 5-HT2A/5-HT6 agonist in a rodent model, and I haven't found much of a point of reference for 5-HT6 agonism outside of cognitive deficits in schizophrenia. Interestingly enough this drug is also being developed for substance abuse disorder, while it does have a pretty ambitious lead indication for dementia (I'm kind of skeptical there)
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u/HYDROMORPHONE_ZONE Jul 21 '26
This is anecdotal but one time while I was still using hydromorphone, I took a light dose of mushrooms, psilocybin, and once it started to kick in, I completely lost the urge to use my drug of choice that was sitting right in front of me. I hadn’t used any that day yet, and iirc I had just restocked right before that so I had plenty anyway. This might be useful
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u/hackyourbios Jul 20 '26
Very interesting, especially after TBG. There is an epidemic in US, so it should help a lot of people
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u/Robert_Larsson Jul 20 '26
News article: https://www.drugdiscoverynews.com/ai-designed-drug-cuts-fentanyl-intake-and-reshapes-brain-circuits-in-preclinical-study-17140
Gotta admit, ibogaine became a lot less cool after Joe Rogan and Rick Perry showed up at the White House. Let's make sure these dorks don't ruin the fun for us!