List of modafinil analogues and derivatives

Chemical structure of modafinil.

This page is a list of modafinil analogues and derivatives, that is, structural analogues and derivatives of the atypical dopamine reuptake inhibitor (DRI) and wakefulness-promoting agent (or "eugeroic") modafinil.[1][2]

Most of the developed modafinil analogues are selective DRIs with improved potency.[3][2][4] They are of interest in the potential treatment of psychostimulant use disorder (PSUD),[3][2][5][6] as pro-motivational agents to treat motivational disorders,[4][7] and for treatment of certain other conditions, like Alzheimer's disease.[8] Modafinil analogues acting as DRIs include both atypical modafinil-like non-psychostimulant DRIs like flmodafinil and JJC8-016 and classical or typical cocaine-like DRIs like JJC8-088.[3][5]

Besides their potential medical use, modafinil analogues, including adrafinil, flmodafinil, fladrafinil, and modafiendz, are also sold online as nootropics or "cognitive enhancers".[1][9][10][11]

A limitation of some modafinil analogues, like JJC8-016, is potent inhibition of the hERG antitarget and predicted cardiotoxicity.[6][2][12][13][14]

  1. ^ a b Sousa A, Dinis-Oliveira RJ (2020). "Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects". Subst Abus. 41 (2): 155–173. doi:10.1080/08897077.2019.1700584. PMID 31951804.
  2. ^ a b c d 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.
  3. ^ a b c 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.
  4. ^ a b Cite error: The named reference SalamoneCorrea2024 was invoked but never defined (see the help page).
  5. ^ a b 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?". Front Neurosci. 15: 656475. doi:10.3389/fnins.2021.656475. PMC 8187604. PMID 34121988.
  6. ^ 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.
  7. ^ Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. 58. Cham: 325–353. doi:10.1007/7854_2022_355. ISBN 978-3-031-09682-2. PMID 35505057.
  8. ^ Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF (2023). "Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease". Front Cell Neurosci. 17: 1292858. doi:10.3389/fncel.2023.1292858. PMC 10679733. PMID 38026688.
  9. ^ Cite error: The named reference SchifanoCatalaniSharif2022 was invoked but never defined (see the help page).
  10. ^ Cite error: The named reference NapoletanoSchifanoCorkery2020 was invoked but never defined (see the help page).
  11. ^ Cite error: The named reference DowlingKavanaghTalbot2017 was invoked but never defined (see the help page).
  12. ^ Rahimi O, Cao J, Lam J, Childers SR, Rais R, Porrino LJ, Newman AH, Nader MA (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.
  13. ^ 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 (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).
  14. ^ 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 (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. PMC 10863442. PMID 38357284.