spec sheet11 rows
JJC8-088 is a modafinil-derived dopamine transporter blocker synthesised at NIDA that was first published as an atypical, low abuse liability lead for cocaine use disorder and was then reclassified by its own lab as the cocaine-like one [2]; rats and monkeys self-administer it, no human has ever taken it, and its role in the literature today is mostly as the typical comparator against its atypical sibling JJC8-091 [4].
- Valuable experimental comparator for understanding DAT-related abuse liability
- Well-characterized dopamine-elevating profile across species
- Advances the atypical dopamine uptake inhibitor research framework
- Stimulant risks such as cardiovascular and psychiatric effects are plausible
Overview
JJC8-088 belongs to a series of modafinil analogs designed by Amy Hauck Newman and colleagues to explore the atypical dopamine uptake inhibitor hypothesis, the idea that some DAT blockers can raise dopamine and reduce psychostimulant seeking without themselves being strongly reinforcing. Within this series, JJC8-088 was deliberately positioned as the higher-affinity, more conventional counterpoint to the atypical JJC8-091 [1][2].
Mechanistic studies showed that despite close structural similarity, JJC8-088 increased extracellular dopamine in the nucleus accumbens shell more potently and efficaciously than JJC8-091 and was more cocaine-like, whereas JJC8-091 was not self-administered by rats [2]. In rhesus monkey choice procedures and reinforcement studies, the two compounds continued to diverge, with JJC8-088 showing the profile predicted to carry greater abuse liability [3][4]. This contrast has made the pair a widely used experimental framework for linking DAT binding kinetics and conformational preference to behavioral outcomes.
JJC8-088 is strictly a research compound. Its scientific value lies less in being a candidate therapeutic and more in serving as the cocaine-like reference against which safer, atypical inhibitors are benchmarked. It has no approved use and no human safety data.
- JJC8-088 and its sibling JJC8-091 are almost twins structurally, yet one behaves like cocaine and the other does not, which is why researchers study them together.
- Both are chemical descendants of modafinil, the wakefulness drug.
Mechanism
JJC8-088 is 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)piperazin-1-yl)-3-phenylpropan-2-ol, reported as compound 11b in the 2016 medicinal chemistry paper that produced the JJC series at the Medicinal Chemistry Section of the NIDA Intramural Research Program [5]. It descends structurally from modafinil: the diphenylmethylsulfinyl core is retained, the rings are fluorinated at the 4 and 4' positions, and the amide of modafinil is replaced by a piperazine carrying a 2-hydroxy-3-phenylpropyl arm [5]. That terminal phenyl is the single feature that separates it from JJC8-091, which carries a plain 2-hydroxypropyl arm instead [2]. It has been dosed in animals as the oxalate salt [2] and as the fumarate salt [8].
The compound is a very high affinity inhibitor. In rat brain tissue against [3H]WIN 35,428 its Ki is 2.53 nM, roughly 30 times tighter than cocaine, which is reported at Ki 72 nM in the head to head comparison [5][6]. It is strongly selective: SERT Ki is 4,610 nM and NET Ki is 15,000 nM, so roughly 1,800 fold and 6,000 fold selectivity over the other two monoamine transporters [5]. It was also screened for binding across 69 receptors, transporters and enzymes at 100 nM and 10 micromolar, with the results reported in supplementary tables rather than singled out as a source of activity for this compound [1]. The nearest named off target sites are sigma-1 at Ki 336 nM, a sigma-1 to ratio of 133, and at Ki 78.6 nM [5]. The number is a binding number only; in a functional assay of quinpirole-stimulated D2 activation of Gi1 the compound was inactive at IC50 above 10,000 nM, so it is at most a very weak D2 and that site is unlikely to shape its behaviour [5]. D3 Ki is 652 nM and D4 Ki is 1,750 nM [5]. Affinity is species dependent in a way that matters for the primate work: in rhesus monkey striatum the Ki is 14.4 nM, about six times weaker than in rat, while JJC8-091 loses far more ground at 2,730 nM [3].
The scientific interest in JJC8-088 is entirely about which shape of the transporter it prefers. cycles through outward-facing, occluded and inward-facing conformations, and the working hypothesis in this field is that cocaine-like reinforcement tracks a preference for the outward-facing state while the atypical, low abuse liability inhibitors push the transporter inward [2][8]. The 2016 paper placed JJC8-088 on the atypical side on the strength of a mutant binding assay: its affinity fell 14.9 fold at the Y156F mutant relative to wild type , close to modafinil's 10 fold and far from cocaine's 1.4 fold [5]. Molecular dynamics simulation three years later reversed that reading. The terminal phenyl group of JJC8-088 was found to lock the transporter in an outward-open conformation, the same state cocaine prefers, while the absence of that group in JJC8-091 lets the transporter relax toward an inward-facing conformation [2]. Every behavioural result since has agreed with the simulation rather than with the mutant assay [3][4].
In vivo the neurochemistry is that of a classical stimulant. Microdialysis in rat nucleus accumbens shell showed extracellular rising roughly 100 percent above baseline at 3 mg/kg and 300 percent at 10 mg/kg, still about 100 percent above baseline three hours after injection [2]. Fast scan cyclic voltammetry in mouse accumbens shell found JJC8-088 slowing clearance to about 30 percent of baseline and raising evoked dopamine to nearly 400 percent of baseline at the top dose, where cocaine in the same experiment reached nearly 300 percent [6]. A later voltammetry study in male and female mice again classed it as a typical inhibitor and found it raised evoked accumbens in both sexes [8]. Locomotor activity follows: dose-effect maxima are comparable to cocaine, with JJC8-088 roughly ten times less potent [6]. The original 2016 report described no significant locomotor response at 10 mg/kg but a significant dose-dependent increase once the dose reached 30 mg/kg [5].
The reward and reinforcement data are the reason the compound is not a medication candidate. Rats with a cocaine self-administration history substituted JJC8-088 for cocaine and kept responding, and drug-naive rats self-administered it intravenously much as they did cocaine, which JJC8-091 did not [2]. Priming injections at 10 and 30 mg/kg produced robust dose-dependent reinstatement of cocaine seeking after extinction, again unlike JJC8-091 [2]. In -cre mice with channelrhodopsin in ventral tegmental neurons, JJC8-088 shifted the optical intracranial self-stimulation rate-frequency curve to the left, the cocaine-like signature of enhanced brain stimulation reward, while JJC8-091 shifted it downward [2]. In rhesus monkeys responding under a progressive ratio schedule JJC8-088 functioned as a reinforcer with reinforcing strength equal to cocaine and with a potency similar to cocaine [4]. It does reduce cocaine self-administration in rats under a fixed ratio schedule at 3, 10 and 30 mg/kg [2], but a drug that suppresses cocaine intake by substituting for it is doing what d-amphetamine does, with the abuse liability that implies [4].
Pharmacokinetics are the other limitation. JJC8-088 barely enters the rodent brain: very little was detectable in rat brain 30 minutes after an intraperitoneal dose and it was nearly undetectable by 120 minutes, despite good plasma levels [1]. That poor brain penetration is the explanation the authors favoured for its complete failure to alter methamphetamine self-administration in rats [1]. Metabolic stability reads differently by species: in mouse liver microsomes only about 4 percent of the compound remained after an hour, an in vitro near 13 minutes, while in rat liver microsomes it was reported as stable [5][1]. In rhesus monkeys given 0.7 mg/kg intravenously the plasma was 1.1 hours with a volume of distribution of 0.96 L/kg and no detectable drug at 24 hours, against 3.5 hours and 7.9 L/kg for JJC8-091 at a threefold higher dose [3].
Several things are simply not established. No study has measured JJC8-088 at the human in a functional uptake assay reported alongside its rodent Ki, so the rat number is doing all the work. No hERG or cardiac electrophysiology data have been published for this compound specifically, which matters because cardiac liability is an acknowledged obstacle for the wider sulfoxide alicyclic amine series it belongs to. No pharmacokinetic or toxicology work exists in any species beyond rat, mouse and macaque, and there is no repeat-dose toxicology, no genotoxicity, no reproductive data and no receptor screen published at concentrations above 10 micromolar. Nothing is known about metabolites, and the sulfoxide is a stereocentre that has never been resolved into single enantiomers for this compound.
receptor fingerprint
()Reuptake inhibitor (higher affinity)
Nucleus accumbens Increase
transporter (SERT)weak inhibitor; not expected to contribute at DAT-occupying doses
transporter (NET)very weak inhibitor
Sigma-1 receptorweak binder; functional consequence untested in vivo
receptorbinds but is functionally inactive; at most a very weak antagonist
D3 receptorweak binder
D4 receptorvery weak binder
Broad off target panel (69 sites)screened; no additional site was singled out as a source of activity for this compound
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
There is no human safety information of any kind. JJC8-088 has never been administered to a person, there is no registered clinical trial for it, and no toxicology package has been published. Nothing below should be read as a human safety profile; it is animal data and it is thin.
The clearest hazard signal is abuse liability, and it is unusually direct evidence. Drug-naive rats self-administered JJC8-088 intravenously in a pattern resembling cocaine [2], priming doses reinstated cocaine seeking after extinction [2], and it enhanced optical brain stimulation reward in mice the way cocaine does [2]. In rhesus monkeys under a progressive ratio schedule it functioned as a reinforcer with reinforcing strength equal to cocaine and comparable potency [4]. A compound that primates will work as hard for as they will for cocaine is a compound with cocaine-like abuse potential.
Chronic dosing in monkeys produced visible unwanted effects. Over nine weeks of intravenous treatment the doses that reduced cocaine choice also produced increased stereotypy and a sharp fall in the total number of reinforcers earned in every monkey tested [3]. Two of three monkeys showed early appetite suppression that faded within a few sessions, and one monkey had a persistent drop in food-maintained responding that did not resolve even when the dose was lowered [3]. The investigators recorded fewer adverse events on JJC8-091 than on JJC8-088 and named the side effect burden as a limitation on developing JJC8-088 as a medication [3].
No cardiac data exist for this compound. hERG channel activity, QT interval and blood pressure have not been reported for JJC8-088 in any species. Sigma-1 affinity at 336 nM is roughly 130 fold weaker than its DAT affinity, so sigma-1 engagement is unlikely at DAT-occupying doses but has not been ruled out in vivo [5][1]. Dopamine D2 binding at 78.6 nM was functionally silent in a Gi1 activation assay, which argues against a meaningful antipsychotic-like or extrapyramidal liability [5].
There is no legitimate route of supply. JJC8-088 is a government laboratory compound synthesised in-house at NIDA for each study [8], it is not commercially distributed as a supplement or a research chemical, and it has no accepted human use. Given the primate self-administration data, anything sold under this name would be a compound with demonstrated cocaine-like reinforcing properties and no human safety record at all.
History
The JJC series came out of a search for a cocaine use disorder medication at the Medicinal Chemistry Section of the NIDA Intramural Research Program. Modafinil binds DAT differently from cocaine and had shown some clinical promise in psychostimulant use disorder, but its affinity for the transporter is weak. The programme set out to keep modafinil's binding mode and add potency by modifying the sulfoxide, fluorinating the rings and replacing the amide with substituted piperazines [5].
JJC8-088 was first published in 2016 as compound 11b, and it was presented as a success. It emerged as the highest affinity and most selective DAT inhibitor in the series at Ki 2.53 nM, its affinity dropped 14.9 fold at the Y156F mutant in the pattern taken to mark atypical binding, and the paper proposed it as a potential lead for development as a psychostimulant abuse medication [5]. The paper's title framed the whole series as atypical dopamine transporter inhibitors [5].
The reclassification happened over the next three years. A 2018 study of methamphetamine self-administration in rats found JJC8-088 had no effect at all in either short access or long access animals, while its siblings JJC8-016 and JJC8-091 both reduced intake [1]. A 2019 voltammetry and microdialysis study in mice found it raised accumbens dopamine and drove locomotion the way cocaine does, and described its profile as that of a typical rather than atypical DAT blocker [6]. The 2019 Neuropsychopharmacology paper then ran the two compounds head to head across self-administration, reinstatement, electrophysiology, optical brain stimulation reward and molecular dynamics, and concluded that JJC8-088 binds DAT in an outward-facing conformation like cocaine while JJC8-091 steers it toward an occluded one [2]. That paper nominated JJC8-091, not JJC8-088, as the compelling candidate for development [2].
Since then JJC8-088 has been used mostly as the typical comparator that makes the atypical case legible. A 2021 review of the modafinil analogue programme summarised its position in one table row: it reduced cocaine self-administration in rats without moving progressive ratio breakpoints, it increased optical intracranial self-stimulation in mice, and it did nothing to methamphetamine self-administration in either short access or long access rats [7]. A 2023 study in rhesus monkeys tested both compounds against cocaine versus food choice and found chronic JJC8-088 could reduce cocaine choice in two of three monkeys, but at the cost of stereotypy and a collapse in reinforcers earned [3]. A 2023 voltammetry study used it as the reference typical inhibitor while examining sex differences in dopamine dynamics [8]. A 2024 study took the series in a different direction and found JJC8-088 reversed a tetrabenazine-induced low-effort bias in rats and increased selection of high-effort progressive ratio responding, raising the possibility that typical DAT inhibitors have a place in effort-related motivational dysfunction even if they are wrong for addiction [9]. A 2025 monkey study closed the loop by showing both JJC compounds function as reinforcers, with JJC8-088 matching cocaine in both reinforcing strength and potency [4].
The literature is small and it belongs almost entirely to one research group. Nine peer-reviewed sources name this compound. It has not entered clinical development and there is no indication that it will.
Reputation
In the addiction pharmacology field JJC8-088 is well known as the cautionary counterpart to JJC8-091; it is cited to illustrate how small structural or binding-mode differences translate into cocaine-like versus atypical behavior. It has no consumer following and is not marketed. Its reputation is that of an instructive but abuse-liable research tool rather than a therapeutic lead.
Subjective profileweighing the evidence above
Valuable to researchers precisely because it is the cocaine-like member of its series, which is also the reason nobody should be taking it. No human data, an abuse-liable profile by design, and stimulant cardiovascular risk on top.
Resources
This entry is here for reference.
Research
- 2016first citedNovel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical…
- 2025most recentContrasting the reinforcing effects of the novel dopamine transport inhibitors JJC8-088 and JJC…
- 1.Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.
- 2.Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders.
- 3.The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.
- 4.Contrasting the reinforcing effects of the novel dopamine transport inhibitors JJC8-088 and JJC8-091 in monkeys: Potential translation to medication assisted treatment.
- 5.Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors.
- 6.Effects of ( R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell.
- 7.Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder.
- 8.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.
- 9.Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.
9 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is JJC8-088 a safer stimulant?
No. Within its research series it is the more cocaine-like, abuse-liable compound; the atypical, lower-abuse counterpart is JJC8-091.
What was it made for?
It was designed at NIDA as a comparator in the search for medications to treat cocaine and methamphetamine use disorders.
Can I use it as a nootropic?
No. It is an experimental stimulant research chemical with abuse liability and no human safety data or approved use.
Is JJC8-088 the same thing as JJC8-091?
No, and mixing them up inverts the whole point of the research. They differ by one benzyl group: JJC8-088 carries a 2-hydroxy-3-phenylpropyl arm on the piperazine, JJC8-091 a plain 2-hydroxypropyl arm [2]. That single group changes which shape of the transporter the molecule prefers. JJC8-088 locks DAT outward-open like cocaine and behaves like cocaine; JJC8-091 lets DAT relax toward an occluded state, is not self-administered by rats, and blocks cocaine-primed reinstatement [2]. JJC8-091 is the medication candidate. JJC8-088 is the control that shows what the candidate is being compared against.
Can I buy it?
No. JJC8-088 is a government laboratory compound made in-house at the NIDA Intramural Research Program for each study that uses it [8]. It is not distributed commercially, it has no approved use anywhere, and it has never been given to a human. Anything offered for sale under this name should be treated as unidentified material, and the identified molecule is one that rhesus monkeys will work as hard to obtain as they work for cocaine [4].
Why was it called atypical if it acts like cocaine?
Because the original evidence pointed that way and better evidence overturned it. In 2016 the compound's affinity fell 14.9 fold at the Y156F DAT mutant, close to modafinil's 10 fold and far from cocaine's 1.4 fold, which was the accepted signature of atypical binding at the time [5]. Molecular dynamics simulation in 2019 showed the terminal phenyl group holds the transporter in an outward-open conformation like cocaine, and the behavioural work agreed [2]. The label stuck to the 2016 paper title and to the series name, so the word atypical still appears next to this compound in places where it no longer applies.
Is it a nootropic or a stimulant?
Neither label has been earned on cognition data, because no cognition study exists. What exists is stimulant pharmacology: dopamine reuptake blockade at Ki 2.53 nM [5], accumbens dopamine up 300 percent at 10 mg/kg in rats [2], and locomotor stimulation with a dose-effect maximum comparable to cocaine [6]. The one motivation-adjacent finding is that it reversed a drug-induced low-effort bias in rats and increased willingness to work for a preferred reward [9], which is an effort-based choice result, not a memory or learning result.
Did it ever reach human trials?
No. There is no registered clinical trial and no published human exposure. The 2019 paper that compared the two siblings explicitly nominated JJC8-091 for development and did not nominate JJC8-088 [2]. The 2023 monkey work then named the side effect burden of chronic JJC8-088, stereotypy and a collapse in reinforcers earned, as a limitation on using it as a medication [3].
How strong is the evidence base?
Thin, and it comes from one place. Nine peer-reviewed sources name this compound, all preclinical except one review, and nearly all of them originate from or collaborate with the same NIDA group. The findings are internally consistent and use good methods, including nonhuman primate self-administration, but no independent laboratory has replicated the core characterisation. Every number on this page is a rodent, mouse or macaque number.
Why did it fail against methamphetamine when its siblings worked?
Probably because it never reached the brain. In rats, very little JJC8-088 was detectable in brain tissue 30 minutes after dosing and it was nearly undetectable by two hours, despite adequate plasma levels [1]. The authors named poor brain penetration as the most parsimonious explanation for its complete lack of effect on methamphetamine self-administration in both short access and long access rats, while noting that its weak sigma-1 affinity relative to DAT could also contribute [1].
Limitations of the evidence
- Cocaine-like, abuse-liable profile in preclinical models
- No human safety data
Adverse effects
- Stimulant risks such as cardiovascular and psychiatric effects are plausible