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| Drug class | Atypical dopamine reuptake inhibitor |
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| Formula | C22H28F2N2O2S |
| Molar mass | 422.53 g·mol−1 |
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JJC8-091 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. [1] [2] [3] [4] 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. [5]
The affinity (Ki) of JJC8-091 for the dopamine transporter (DAT) is 230 to 289 nM. [5] [1] [6] [7] In another study however, its affinities for the monoamine transporters were 16.7 nM for the DAT, 17,800 nM for the norepinephrine transporter (NET) (1,066-fold lower than for the DAT), and 1,770 nM for the serotonin transporter (SERT) (106-fold lower than for the DAT). [2] It has substantially higher affinity for the DAT than modafinil (Ki = 2,600–8,160 nM). [2] [5] Besides the DAT, JJC8-091 is a sigma σ1 receptor ligand (Ki = 454–1,010 nM; 2.0–3.5-fold lower than for the DAT). [5] [6] [7] [8] It also has high affinity for the dopamine D2 and D3 receptors and lower affinity for the dopamine D4 receptor (Ki = 298 nM, 480 nM, and 3,820 nM, respectively). [7]
JJC8-091 results in a mild, slow-onset, long-duration increase in dopamine levels in the nucleus accumbens in animals. [1] [3] 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). [4] JJC8-091 does not increase locomotor activity in animals, is not self-administered, and does not substitute for cocaine, suggesting very low addictive potential. [3] [4] [1] Additionally, it reduces cocaine and methamphetamine self-administration, decreases escalation of methamphetamine intake, and blocks cocaine-induced reinstatement of drug-seeking behaviors. [3] [1] [5] [4] Unlike analogues including JJC8-088, JJC8-089, and RDS03-94, JJC8-091 did not show pro-motivational effects in animals. [9] [10]
JJC8-091 was first described in the scientific literature by 2016. [7] It shows a favorable predicted drug-like profile in terms of metabolism and pharmacokinetics. [1] [7] However, JJC8-091, similarly to analogues like JJC8-016, has been found to exert hERG inhibition. [11] In any case, modafinil and novel analogues like JJC8-091 are of interest in the potential treatment of PSUD. [12] [1] [5]