JJC8-016

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

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.

JJC8-016 was under investigation for the potential treatment of PSUD.{{cite journal | vauthors = Jordan CJ, Cao J, Newman AH, Xi ZX | title = Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine | journal = Neuropharmacology | volume = 158 | issue = | pages = 107609 | date = November 2019 | pmid = 31009632 | pmc = 6745247 | doi = 10.1016/j.neuropharm.2019.04.015 | url = }} However, it was abandoned following findings that it interacts with high affinity at the hERG antitarget ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} = 60{{nbsp}}nM) and thereby would be predicted to produce cardiotoxicity.{{cite book | vauthors = Aggarwal S, Mortensen OV | chapter = Discovery and Development of Monoamine Transporter Ligands | series = Advances in Neurobiology | title = Drug Development in Psychiatry | journal = Adv Neurobiol | volume = 30 | issue = | pages = 101–129 | date = 2023 | location = Cham | pmid = 36928847 | pmc = 10074400 | doi = 10.1007/978-3-031-21054-9_4 | isbn = 978-3-031-21053-2 | chapter-url = }}{{cite journal | vauthors = Rahimi O, Cao J, Lam J, Childers SR, Rais R, Porrino LJ, Newman AH, Nader MA | title = The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys | journal = J Pharmacol Exp Ther | volume = 384 | issue = 3 | pages = 372–381 | date = March 2023 | pmid = 36507847 | pmc = 9976790 | doi = 10.1124/jpet.122.001363 | url = | quote = However, JJC8-016 failed cardiac safety tests by exhibiting relatively high affinity at hERG channels; thus, this analog was abandoned from further development.}} This was also the reason for the abandonment of vanoxerine (GBR-12909), a structurally distinct atypical DRI that was in clinical trials for PSUD.{{cite journal | vauthors = Rothman RB, Baumann MH, Prisinzano TE, Newman AH | title = Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction | journal = Biochem Pharmacol | volume = 75 | issue = 1 | pages = 2–16 | date = January 2008 | pmid = 17897630 | pmc = 2225585 | doi = 10.1016/j.bcp.2007.08.007 | url = }} 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.{{cite journal | vauthors = 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 | title = Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach | journal = J Chem Inf Model | volume = 61 | issue = 9 | pages = 4266–4279 | date = September 2021 | pmid = 34420294 | pmc = 9593962 | doi = 10.1021/acs.jcim.1c00856 | url = | quote = 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).}} 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.{{cite journal | vauthors = 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 | title = Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity | journal = ACS Pharmacol Transl Sci | volume = 7 | issue = 2 | pages = 515–532 | date = February 2024 | pmid = 38357284 | doi = 10.1021/acsptsci.3c00322 | pmc = 10863442 | url = }}

JJC8-016 was first described in the scientific literature by 2014.{{cite journal | vauthors = Okunola-Bakare OM, Cao J, Kopajtic T, Katz JL, Loland CJ, Shi L, Newman AH | title = Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues | journal = J Med Chem | volume = 57 | issue = 3 | pages = 1000–1013 | date = February 2014 | pmid = 24494745 | pmc = 3954497 | doi = 10.1021/jm401754x | url = }} However, the actual compound itself was first mentioned in a patent that dates back to 1992.Patricia Caldirola, Raimund Mannhold, & Hendrik Timmerman, US5171752 (1992 to Organon NV).

• List of modafinil analogues and derivatives

{{Reflist}}

{{Monoamine reuptake inhibitors}}

{{Dopamine receptor modulators}}

{{Sigma receptor modulators}}

{{Ion channel modulators}}

Category:4-Fluorophenyl compounds

Category:Abandoned drugs

Category:Secondary amines

Category:Dopamine receptor modulators

Category:Dopamine reuptake inhibitors

Category:HERG blocker

Category:Organosulfur compounds

Category:Serotonin reuptake inhibitors

Category:Sigma receptor modulators

Category:Modafinil analogues