AI-derived therapeutic development of a serotonin receptor-targeting drug for the treatment of opioid use disorder

Clinical Snapshot

Key Findings

• P Value: Not reported (described as 'significant')

• Effect Size: Not reported in abstract

• Primary Outcome: Significant decrease in fentanyl intake in both male and female rats

• Nnt Or Sensitivity: Not applicable for preclinical study

• Confidence Interval: Not reported

Clinical Application

Requires extensive Phase I-III clinical trials before any clinical application Would require TGA approval through standard drug development pathway. Relevant to Australian opioid crisis, particularly given PBS coverage considerations for addiction treatments and RACGP guidelines on opioid use disorder management Currently not applicable - preclinical stage only

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.

References

1. 1.Lallai, V., Kho, S., Martin, A. C., Fowler, J. P., Roach, M. L., Wang, K., Laumann, K. N., Morrison, T. G., Palaniappan, M., Bautista, M., Mogul, A. S., Cheepluesak, J. E., Shrestha, B., Lade, D. M., Lagomarsino, J. E., Narayan, V., Uffens, J., Lernhardt, W., Mirzaei, S., Jenkins, I., Zavala, A. R., Lakey, J. R. T., Tinder, R., & Fowler, C. D. (2026). AI-derived therapeutic development of a serotonin receptor-targeting drug for the treatment of opioid use disorder. Proceedings of the National Academy of Sciences, 123, Article 2516807123. https://doi.org/10.1073/pnas.2516807123