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| Clinical data | |
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| Drug class | Typicaldopamine reuptake inhibitor |
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| Chemical and physical data | |
| Formula | C28H32F2N2O2S |
| Molar mass | 498.63 g·mol−1 |
| 3D model (JSmol) | |
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JJC8-088 is adopamine reuptake inhibitor (DRI) that wasderived from thewakefulness-promoting agentmodafinil.[1][2][3]
It has substantially higheraffinity for thedopamine transporter (DAT) than modafinil (Ki = 6.72 nM vs. 2,600 nM; 387-fold).[2] In contrast to modafinil and otheranalogues, which are atypical DRIs, JJC8-088 is a typicalcocaine-like DRI.[1][3] It haspotent cocaine-likepsychostimulant effects, produces robust anddose-dependent increases indopamine levels in thenucleus accumbens, and is readilyself-administered by and substitutes for cocaine in animals.[1][3]
Similarly to cocaine, but unlike modafinil and other analogues, JJC8-088 stabilizes the DAT in an outward-facing open conformation.[1] It has been theorized that cocaine-like DRIs may actually act asdopamine releasing agent-like DAT "inverse agonists" rather than as simpletransporter blockers.[4]
In addition to its affinity for the DAT, JJC8-088 has low affinity for theserotonin transporter (SERT) (Ki = 213 nM; 32-fold less than for the DAT) and for thenorepinephrine transporter (NET) (Ki = 1950 nM; 290-fold less than for the DAT).[2] It also binds with high affinity to thesigmaσ1 receptor (Ki = 41.6 nM).[5]
The drug has high affinity for thehERGantitarget (IC50Tooltip half-maximal inhibitory concentration = 130 nM) and could producecardiotoxicity,[6][7] which might cause a risk ofheart attack if JJC8-088 were to be used recreationally.[8][9]
From this validation set of DAT inhibitors, we noticed that a pair of analogs with similar chemical structures, JJC8-01646 and JJC8-08813 (Tanimoto similarity = 0.62, Figure S6), have opposite trends of affinities at DAT and hERG. JJC8-088 has ~90-fold higher affinity than JJC8-016 at DAT (Ki = 2.6 and 234.4 nM, respectively), but has ~2-fold lower affinity than JJC8-016 at hERG (IC50 = 0.13 and 0.06 μM, respectively).