JJC8-091

JJC8-091 is a modafinil-derived diphenylmethyl-sulfinyl compound bearing bis(4-fluorophenyl) and a hydroxypropyl-piperazine moiety (CAS 1627576-76-4; molecular formula C22H28F2N2O2S). It was designed at the U.S. National Institute on Drug Abuse as part of a program probing the atypical dopamine uptake inhibitor hypothesis, which holds that inhibitors stabilizing a more inward-facing dopamine transporter (DAT) conformation elevate dopamine slowly and lack cocaine-like reinforcement, making them candidate medications for psychostimulant use disorder.

JJC8-091 binds DAT with reported affinities around 230 to 289 nM in rats (and far weaker, near 2730 nM, in primate striatum), with much lower affinity for the norepinephrine and serotonin transporters and moderate sigma-1 receptor binding. A close structural analogue, JJC8-088, differs only subtly yet behaves as a typical, cocaine-like inhibitor with higher DAT affinity and abuse liability, illustrating how small template changes flip the pharmacological class.

In rhesus monkeys under a cocaine-versus-food choice schedule, acute JJC8-091 shifted the cocaine dose-response curve but only modestly reduced cocaine choice, and the rat-to-monkey translation was limited by the affinity difference. A later self-administration study found both JJC compounds could function as reinforcers under some conditions, but when an alternative reinforcer (food) was available, JJC8-091 was not chosen over food, supporting substantially lower abuse liability than cocaine.

Fast-scan cyclic voltammetry showed JJC8-091 produced only limited increases in evoked nucleus accumbens dopamine and slowed clearance, and it was more effective than JJC8-088 at blunting cocaine-mediated dopamine enhancement, consistent with its atypical, inward-facing-preferring conformation. Optimization continues because JJC8-091 inhibits the hERG cardiac channel. It is strictly a preclinical medication-development candidate with no human data.

No human safety data exist. The principal identified liability is inhibition of the hERG potassium channel, a cardiac repolarization risk that has driven further chemical optimization. In animals JJC8-091 was largely non-reinforcing when an alternative reward was available, but it was self-administered under some conditions, so its abuse liability is best described as low relative to cocaine rather than absent. It remains an investigational compound with no clinical toxicology.

JJC8-091 was synthesized in the medicinal-chemistry program of Amy Hauck Newman and colleagues at NIDA and first described in the scientific literature around 2016 as part of a series testing the atypical DAT inhibitor hypothesis. It was subsequently advanced by EncepHeal Therapeutics as a lead for cocaine use disorder, with behavioral and pharmacokinetic evaluations in rats and nonhuman primates published through the early 2020s.

In the addiction-pharmacology field JJC8-091 is a well-known tool compound and medication-development candidate that helped validate the idea that DAT inhibitors can be engineered to lack cocaine-like reinforcement. It has no standing as a recreational or nootropic substance and is not sold to consumers.