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]
^ 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 .
^ 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 .
^ 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 .
^ a b Cite error: The named reference SalamoneCorrea2024
was invoked but never defined (see the help page ).
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ Cite error: The named reference SchifanoCatalaniSharif2022
was invoked but never defined (see the help page ).
^ Cite error: The named reference NapoletanoSchifanoCorkery2020
was invoked but never defined (see the help page ).
^ Cite error: The named reference DowlingKavanaghTalbot2017
was invoked but never defined (see the help page ).
^ 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.
^ 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).
^ 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 .