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) (Ki = 213nM; 32-fold less than for the DAT) and for the norepinephrine transporter (NET) (Ki = 1950nM; 290-fold less than for the DAT).[2] It also binds with high affinity to the sigmaσ1 receptor (Ki = 41.6nM).[5]
^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. PMC9593962. PMID34420294. 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. PMID38357284.