JJC8-091 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is a lead compound for potential treatment of psychostimulant use disorder (PSUD) and is under development by Encepheal Therapeutics for use as a pharmaceutical drug.
The affinity (K<sub>i</sub>) of JJC8-091 for the dopamine transporter (DAT) is 230 to 289nM. In another study however, its affinities for the monoamine transporters were 16.7nM for the DAT, 17,800nM for the norepinephrine transporter (NET) (1,066-fold lower than for the DAT), and 1,770nM for the serotonin transporter (SERT) (106-fold lower than for the DAT). It has substantially higher affinity for the DAT than modafinil (K<sub>i</sub> = 2,600âÂÂ8,160nM). Besides the DAT, JJC8-091 is a sigma ÃÂ<sub>1</sub> receptor ligand (K<sub>i</sub> = 454âÂÂ1,010nM; 2.0âÂÂ3.5-fold lower than for the DAT). It also has high affinity for the dopamine D<sub>2</sub> and D<sub>3</sub> receptors and lower affinity for the dopamine D<sub>4</sub> receptor (K<sub>i</sub> = 298nM, 480nM, and 3,820nM, respectively).
JJC8-091 results in a mild, slow-onset, long-duration increase in dopamine levels in the nucleus accumbens in animals. The increases in nucleus accumbens dopamine levels with JJC8-091 are blunted relative to those with cocaine and JJC8-088 (a cocaine-like DRI) but are greater than those of JJC8-016 (an atypical DRI). JJC8-091 does not increase locomotor activity in animals, is not self-administered, and does not substitute for cocaine, suggesting very low addictive potential. Additionally, it reduces cocaine and methamphetamine self-administration, decreases escalation of methamphetamine intake, and blocks cocaine-induced reinstatement of drug-seeking behaviors. Unlike analogues including JJC8-088, JJC8-089, and RDS03-94, JJC8-091 did not show pro-motivational effects in animals.
JJC8-091 was first described in the scientific literature by 2016. It shows a favorable predicted drug-like profile in terms of metabolism and pharmacokinetics. However, JJC8-091, similarly to analogues like JJC8-016, has been found to exert hERG inhibition. In any case, modafinil and novel analogues like JJC8-091 are of interest in the potential treatment of PSUD.