JJC8-088
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| Formula | C28H32F2N2O2S |
| Molar mass | 498.63 g·mol−1 |
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JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.[1][2][3]
It has substantially higher affinity for the dopamine transporter (DAT) than modafinil (Ki = 6.72 nM vs. 2,600 nM; 387-fold).[2] In contrast to modafinil and other analogues, which are atypical DRIs, JJC8-088 is a typical cocaine-like DRI.[1][3] It has potent cocaine-like psychostimulant effects, produces robust and dose-dependent increases in dopamine levels in the nucleus accumbens, and is readily self-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 as dopamine releasing agent-like DAT "inverse agonists" rather than as simple transporter blockers.[4]
In addition to its affinity for the DAT, JJC8-088 has low affinity for the serotonin transporter (SERT) (Ki = 213 nM; 32-fold less than for the DAT) and for the norepinephrine transporter (NET) (Ki = 1950 nM; 290-fold less than for the DAT).[2] It also binds with high affinity to the sigma σ1 receptor (Ki = 41.6 nM).[5]
See also
[edit]References
[edit]- ^ a b c d Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Current Opinion in Pharmacology. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC 8247144. PMID 32927246.
- ^ a b c Aggarwal S, Mortensen OV (2023). "Discovery and Development of Monoamine Transporter Ligands". Drug Development in Psychiatry. Advances in Neurobiology. Vol. 30. pp. 101–129. doi:10.1007/978-3-031-21054-9_4. ISBN 978-3-031-21053-2. PMC 10074400. PMID 36928847.
- ^ a b c Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G (2021). "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Frontiers in Neuroscience. 15: 656475. doi:10.3389/fnins.2021.656475. PMC 8187604. PMID 34121988.
- ^ Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID 24953830.
- ^ Newman AH, Ku T, Jordan CJ, Bonifazi A, Xi ZX (January 2021). "New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders". Annu Rev Pharmacol Toxicol. 61: 609–628. doi:10.1146/annurev-pharmtox-030220-124205. PMC 9341034. PMID 33411583.