JJC8-088

JJC8-088
Clinical data
Drug class	Typical dopamine reuptake inhibitor
Identifiers
	IUPAC name 1-[4-[2-[bis(4-fluorophenyl)methylsulfinyl]ethyl]piperazin-1-yl]-3-phenylpropan-2-ol;
CAS Number	1627576-82-2;
PubChem CID	118643968;
ChemSpider	76717749;
ChEMBL	ChEMBL3918282;
Chemical and physical data
Formula	C28H32F2N2O2S
Molar mass	498.63 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CN(CCN1CCS(=O)C(C2=CC=C(C=C2)F)C3=CC=C(C=C3)F)CC(CC4=CC=CC=C4)O;
	InChI InChI=1S/C28H32F2N2O2S/c29-25-10-6-23(7-11-25)28(24-8-12-26(30)13-9-24)35(34)19-18-31-14-16-32(17-15-31)21-27(33)20-22-4-2-1-3-5-22/h1-13,27-28,33H,14-21H2; Key:MACFTPBZAOCTFN-UHFFFAOYSA-N;

JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.^[1]^[2]^[3]

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It has substantially higher affinity for the dopamine transporter (DAT) than modafinil (K_i = 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) (K_i = 213 nM; 32-fold less than for the DAT) and for the norepinephrine transporter (NET) (K_i = 1950 nM; 290-fold less than for the DAT).^[2] It also binds with high affinity to the sigma σ₁ receptor (K_i = 41.6 nM).^[5]

The drug has high affinity for the hERG antitarget (IC₅₀Tooltip half-maximal inhibitory concentration = 130 nM) and could produce cardiotoxicity,^[6]^[7] which might cause a risk of heart attack if JJC8-088 were to be used recreationally.^[8]^[9]

[1]
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.
[2]
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.
[3]
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.
[4]
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.
[5]
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.
[6]
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).
[7]
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.
[8]
Furutani K. Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk. Int. J. Mol. Sci. 2023; 24(22): 16261. doi:10.3390/ijms242216261
[9]
Creanza TM, et al. Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study. J.Chem. Inf.Model. 2021; 61:4758−4770. {{doi:10.1021/acs.jcim.1c00744}}

[TandaHerseyHempel2021-1] [1]
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.

[AggarwalMortensen2023-2] [2]
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.

[HerseyBaconBailey2021-3] [3]
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.

[HealGosdenSmith2014-4] [4]
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.

[NewmanKuJordan2021-5] [5]
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.

[LeeFantGuo2021-6] [6]
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).

[KuCaoWon2024-7] [7]
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.

[8] [8]
Furutani K. Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk. Int. J. Mol. Sci. 2023; 24(22): 16261. doi:10.3390/ijms242216261

[9] [9]
Creanza TM, et al. Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study. J.Chem. Inf.Model. 2021; 61:4758−4770. {{doi:10.1021/acs.jcim.1c00744}}

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JJC8-088

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