JJC8-016
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| Drug class | Atypical dopamine reuptake inhibitor |
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| Formula | C24H25F2NS |
| Molar mass | 397.53 g·mol−1 |
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JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil.[1][2][3][4] It was an early lead in the development of novel modafinil analogues with improved properties for potential use in the treatment of psychostimulant use disorder (PSUD).[1][3]
Pharmacology
[edit]The affinities of JJC8-016 for the monoamine transporters are 114 nM for the dopamine transporter (DAT), 3850 nM for the norepinephrine transporter (NET) (34-fold lower than for the DAT), and 354 nM for the serotonin transporter (SERT) (3.1-fold lower than for the DAT).[5][6][4] JJC8-016 also has high affinity for the dopamine D2 receptor (Ki = 228 nM), the dopamine D3 receptor (Ki = 65.9 nM), the dopamine D4 receptor (Ki = 28.1 nM), and the sigma σ1 receptor (Ki = 159 nM).[4] It has much higher affinity for the DAT than modafinil (Ki = 2600 nM; 23-fold difference), but is also much less selective in comparison.[5][4]
Animal studies
[edit]JJC8-016 does significantly modify dopamine levels in the nucleus accumbens, does not produce cocaine- or psychostimulant-like effects, and is not self-administered in animals.[1][3][7] As such, it shows a profile of low misuse liability.[7] Its actions are in contrast to modafinil and other analogues, which do significantly increase nucleus accumbens dopamine levels, albeit much less robustly than cocaine.[1] JJC8-016 has been found to blunt cocaine-mediated increases in dopamine levels in the nucleus accumbens, to dose-dependently block the psychostimulant-like effects of cocaine, to block self-administration of cocaine, and to prevent cocaine-induced reinstatement of drug-seeking behavior in animals.[5][1][3][7] It has also been found to reduce methamphetamine self-administration and escalation of its intake.[1][3]
Preclinical development
[edit]JJC8-016 was under investigation for the potential treatment of PSUD.[7] However, it was abandoned following findings that it interacts with high affinity at the hERG antitarget (IC50 = 60 nM) and thereby would be predicted to produce cardiotoxicity.[2][5][8][9] This was also the reason for the abandonment of vanoxerine (GBR-12909), a structurally distinct atypical DRI that was in clinical trials for PSUD.[5][10] In addition to its hERG affinity, JJC8-016 was described as having poor metabolic and pharmacokinetic characteristics.[7] Subsequently, more selective modafinil-derived DAT blockers, like JJC8-088 and JJC8-091, were developed.[1][9] JJC8-088 has ~90-fold higher affinity for the DAT than JJC8-016 and ~2-fold lower affinity for the hERG.[9] Newer related modafinil analogues and DRIs with further reduced affinity for the hERG were also subsequently developed.[11]
JJC8-016 was first described in the scientific literature by 2014.[6][4]
References
[edit]- ^ a b c d e f g 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". Curr Opin Pharmacol. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC 8247144. PMID 32927246.
- ^ a b 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 (1): 609–628. doi:10.1146/annurev-pharmtox-030220-124205. PMC 9341034. PMID 33411583.
- ^ a b c d e Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, et al. (2021). "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Front Neurosci. 15: 656475. doi:10.3389/fnins.2021.656475. PMC 8187604. PMID 34121988.
- ^ a b c d e Zhang HY, Bi GH, Yang HJ, He Y, Xue G, Cao J, et al. (August 2017). "The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic". Neuropsychopharmacology. 42 (9): 1871–1883. doi:10.1038/npp.2017.41. PMC 5564383. PMID 28266501.
- ^ a b c d e Aggarwal S, Mortensen OV (2023). "Discovery and Development of Monoamine Transporter Ligands". Adv Neurobiol. 30. Cham: 101–129. doi:10.1007/978-3-031-21054-9_4. ISBN 978-3-031-21053-2. PMC 10074400. PMID 36928847.
- ^ a b Okunola-Bakare OM, Cao J, Kopajtic T, Katz JL, Loland CJ, Shi L, et al. (February 2014). "Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues". J Med Chem. 57 (3): 1000–1013. doi:10.1021/jm401754x. PMC 3954497. PMID 24494745.
- ^ a b c d e Jordan CJ, Cao J, Newman AH, Xi ZX (November 2019). "Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine". Neuropharmacology. 158: 107609. doi:10.1016/j.neuropharm.2019.04.015. PMC 6745247. PMID 31009632.
- ^ Rahimi O, Cao J, Lam J, Childers SR, Rais R, Porrino LJ, et al. (March 2023). "The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys". J Pharmacol Exp Ther. 384 (3): 372–381. doi:10.1124/jpet.122.001363. PMC 9976790. PMID 36507847.
However, JJC8-016 failed cardiac safety tests by exhibiting relatively high affinity at hERG channels; thus, this analog was abandoned from further development.
- ^ a b c Lee KH, Fant AD, Guo J, Guan A, Jung J, Kudaibergenova M, et al. (September 2021). "Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach". J Chem Inf Model. 61 (9): 4266–4279. doi:10.1021/acs.jcim.1c00856. PMC 9593962. PMID 34420294.
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).
- ^ Rothman RB, Baumann MH, Prisinzano TE, Newman AH (January 2008). "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochem Pharmacol. 75 (1): 2–16. doi:10.1016/j.bcp.2007.08.007. PMC 2225585. PMID 17897630.
- ^ Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV, et al. (February 2024). "Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity". ACS Pharmacol Transl Sci. 7 (2): 515–532. doi:10.1021/acsptsci.3c00322. PMID 38357284.