ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2019
Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 49 citations in OpenAlex.
- A Series of Aryl-Substituted-(biphenyl)methyl-sulfinylmethylthiazoles as Novel and Atypical Dopamine Transporter Inhibitors.Journal of medicinal chemistry · 2026Article
- From dual norepinephrine-dopamine reuptake inhibition to selective dopamine reuptake inhibitors: a case of aromatically substitutedRSC medicinal chemistry · 2026Article
- The impact of sex, species, environmental context, and alternative reinforcers in animal models of cocaine use disorders.Pharmacology, biochemistry, and behavior · 2025Review
- RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals.Translational psychiatry · 2025Article
- Article
- Novel Ways of Targeting the Dopamine Transporter.Advances in neurobiology · 2025Review
- Contrasting the reinforcing effects of the novel dopamine transport inhibitors JJC8-088 and JJC8-091 in monkeys: Potential translation to medication assisted treatment.The Journal of pharmacology and experimental therapeutics · 2025Article
- AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.The European journal of neuroscience · 2024Article
- Optical Intracranial Self-Stimulation (oICSS): A New Behavioral Model for Studying Drug Reward and Aversion in Rodents.International journal of molecular sciences · 2024Review
- Article
- Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.ACS pharmacology & translational science · 2024Article
- Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.Journal of medicinal chemistry · 2024Article
- Modafinil, an atypical CNS stimulant?Advances in pharmacology (San Diego, Calif.) · 2024Article
- Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry.Biomolecules · 2023Article
- An FSCV Study on the Effects of Targeted Typical and Atypical DAT Inhibition on Dopamine Dynamics in the Nucleus Accumbens Shell of Male and Female Mice.ACS chemical neuroscience · 2023Article
- Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.Molecules (Basel, Switzerland) · 2023Review
- Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.Translational psychiatry · 2023Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.