A novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals.

Omar Soler-Cedeno, Ph.D.

Featured Paper of the Month – December 2025

Published in Translational Psychiatry by Omar Soler-Cedeño and Zheng-Xiong Xi, M.D., Ph.D. of the NIDA IRP Addiction Biology Unit.

Summary

Cocaine addiction remains a major health challenge with no FDA-approved medications. This study evaluated two new compounds in animal models: RDS-04-010, an atypical dopamine transporter (DAT) inhibitor that binds to an inward-facing conformation of DAT, and RDS-03-094, a more typical DAT inhibitor that binds to an outward-facing conformation. Notably, RDS-04-010 reduced cocaine use, lowered motivation to seek cocaine, and prevented relapse-like behavior, while showing no rewarding or addictive effects on its own. In contrast, RDS-03-094 behaved more like cocaine and displayed addictive potential. These findings highlight RDS-04-010 as a promising treatment candidate and show how subtle differences in DAT binding can differentially influence cocaine-related behaviors.

Publication Information

Soler-Cedeno, Omar; Galaj, Ewa; Klein, Benjamin; Cao, Jianjing; Bi, Guo-Hua; Newman, Amy Hauck; Xi, Zheng-Xiong

RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals Journal Article

In: Transl Psychiatry, vol. 15, no. 1, pp. 182, 2025, ISSN: 2158-3188.

Abstract | Links

@article{pmid40413193,

title = {RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals},

author = {Omar Soler-Cedeno and Ewa Galaj and Benjamin Klein and Jianjing Cao and Guo-Hua Bi and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/40413193/},

doi = {10.1038/s41398-025-03391-7},

issn = {2158-3188},

year  = {2025},

date = {2025-05-01},

urldate = {2025-05-01},

journal = {Transl Psychiatry},

volume = {15},

number = {1},

pages = {182},

abstract = {Cocaine use disorder (CUD) is a severe public health problem, and currently, there is no FDA-approved medication for its treatment. Atypical dopamine (DA) transporter (DAT) inhibitors display low addictive liability by themselves and may have therapeutic potential for treatment of psychostimulant use disorders. Here, we report that RDS-04-010, a novel atypical DAT inhibitor that binds to an inward-facing conformation of DAT due to its sulfoxide moiety, displayed distinct pharmacological profiles in animal models of addiction from its sulfide analog, RDS-03-094, a DAT inhibitor that binds to a more outward-facing conformation. Systemic administration of RDS-04-010 dose-dependently inhibited cocaine self-administration, shifted the cocaine self-administration dose-response curve downward, decreased motivation for cocaine seeking under progressive-ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS-04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS-04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. In contrast, RDS-03-094 displayed more cocaine-like reinforcing effects. Its pretreatment upward-shifted both the cocaine self-administration dose-response and optical brain-stimulation reward curves. RDS-03-094 alone was able to reinstate extinguished cocaine-seeking behavior and sustain self-administration during a substitution test. Collectively, these findings suggest that RDS-04-010 is a novel atypical DAT inhibitor with favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. Moreover, this extensive behavioral evaluation further confirms the role that DAT binding conformation plays in the distinctive profiles of atypical DAT inhibitors that prefer the inward facing conformation.},

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pubstate = {published},

tppubtype = {article}

}