JJC8-016 explained

JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) 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).

Pharmacology

The affinities of JJC8-016 for the monoamine transporters are 114nM for the dopamine transporter (DAT), 3850nM for the norepinephrine transporter (NET) (34-fold lower than for the DAT), and 354nM for the serotonin transporter (SERT) (3.1-fold lower than for the DAT). JJC8-016 also has high affinity for the dopamine D₂ receptor (K_i = 228nM), the dopamine D₃ receptor (K_i = 65.9nM), the dopamine D₄ receptor (K_i = 28.1nM), and the sigma σ₁ receptor (K_i = 159nM). It has much higher affinity for the DAT than modafinil (K_i = 2600nM; 23-fold difference), but is also much less selective in comparison.

Animal studies

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. As such, it shows a profile of low misuse liability. Its actions are in contrast to modafinil and other analogues, which do significantly increase nucleus accumbens dopamine levels, albeit much less robustly than cocaine. 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. It has also been found to reduce methamphetamine self-administration and escalation of its intake.

Preclinical development

JJC8-016 was under investigation for the potential treatment of PSUD.^[5] However, it was abandoned following findings that it interacts with high affinity at the hERG antitarget (= 60nM) and thereby would be predicted to produce cardiotoxicity.^{[6] [7]} This was also the reason for the abandonment of vanoxerine (GBR-12909), a structurally distinct atypical DRI that was in clinical trials for PSUD.^[8] In addition to its hERG affinity, JJC8-016 was described as having poor metabolic and pharmacokinetic characteristics. Subsequently, more selective modafinil-derived DAT blockers, like JJC8-088 and JJC8-091, were developed.^[9] JJC8-088 has ~90-fold higher affinity for the DAT than JJC8-016 and ~2-fold lower affinity for the hERG. Newer related modafinil analogues and DRIs with further reduced affinity for the hERG were also subsequently developed.^[10]

JJC8-016 was first described in the scientific literature by 2014.^[11]

See also

• List of modafinil analogues and derivatives

Notes and References

1. Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH . Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder . Curr Opin Pharmacol . 56 . 13–21 . February 2021 . 32927246 . 8247144 . 10.1016/j.coph.2020.07.007 .
2. Newman AH, Ku T, Jordan CJ, Bonifazi A, Xi ZX . New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders . Annu Rev Pharmacol Toxicol . 61 . 1. 609–628 . January 2021 . 33411583 . 9341034 . 10.1146/annurev-pharmtox-030220-124205 .
3. Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G . Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap? . Front Neurosci . 15 . 656475 . 2021 . 34121988 . 8187604 . 10.3389/fnins.2021.656475 . free .
4. Zhang HY, Bi GH, Yang HJ, He Y, Xue G, Cao J, Tanda G, Gardner EL, Newman AH, Xi ZX . The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic . Neuropsychopharmacology . 42 . 9 . 1871–1883 . August 2017 . 28266501 . 5564383 . 10.1038/npp.2017.41 .
5. Jordan CJ, Cao J, Newman AH, Xi ZX . Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine . Neuropharmacology . 158 . 107609 . November 2019 . 31009632 . 6745247 . 10.1016/j.neuropharm.2019.04.015 .
6. Book: Aggarwal S, Mortensen OV . Discovery and Development of Monoamine Transporter Ligands . Advances in Neurobiology . Drug Development in Psychiatry . Adv Neurobiol . 30 . 101–129 . 2023 . Cham . 36928847 . 10074400 . 10.1007/978-3-031-21054-9_4 . 978-3-031-21053-2 .
7. Rahimi O, Cao J, Lam J, Childers SR, Rais R, Porrino LJ, Newman AH, Nader MA . 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 . March 2023 . 36507847 . 9976790 . 10.1124/jpet.122.001363 . However, JJC8-016 failed cardiac safety tests by exhibiting relatively high affinity at hERG channels; thus, this analog was abandoned from further development..
8. Rothman RB, Baumann MH, Prisinzano TE, Newman AH . Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction . Biochem Pharmacol . 75 . 1 . 2–16 . January 2008 . 17897630 . 2225585 . 10.1016/j.bcp.2007.08.007 .
9. Lee KH, Fant AD, Guo J, Guan A, Jung J, Kudaibergenova M, Miranda WE, Ku T, Cao J, Wacker S, Duff HJ, Newman AH, Noskov SY, Shi L . Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach . J Chem Inf Model . 61 . 9 . 4266–4279 . September 2021 . 34420294 . 9593962 . 10.1021/acs.jcim.1c00856 . 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)..
10. Ku TC, Cao J, Won SJ, Guo J, Camacho-Hernandez GA, Okorom AV, Salomon KW, Lee KH, Loland CJ, Duff HJ, Shi L, Newman AH . 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 . February 2024 . 38357284 . 10.1021/acsptsci.3c00322 . 10863442 . January 5, 2025 .
11. Okunola-Bakare OM, Cao J, Kopajtic T, Katz JL, Loland CJ, Shi L, Newman AH . Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues . J Med Chem . 57 . 3 . 1000–1013 . February 2014 . 24494745 . 3954497 . 10.1021/jm401754x .