Chemistry:JJC8-016
JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) derived from modafinil.[1][2][3][4] It was an early lead in the development of novel modafinil analogues with improved properties for potential use in the treatment of psychostimulant use disorder (PSUD).[1][3]
Pharmacology
The affinities of JJC8-016 for the monoamine transporters are 114 nM for the dopamine transporter (DAT), 3850 nM for the norepinephrine transporter (NET) (34-fold lower than for the DAT), and 354 nM for the serotonin transporter (SERT) (3.1-fold lower than for the DAT).[5][6][4] JJC8-016 also has high affinity for the dopamine D2 receptor (Ki = 228 nM), the dopamine D3 receptor (Ki = 65.9 nM), the dopamine D4 receptor (Ki = 28.1 nM), and the sigma σ1 receptor (Ki = 159 nM).[4] It has much higher affinity for the DAT than modafinil (Ki = 2600 nM; 23-fold difference), but is also much less selective in comparison.[5][4]
Animal studies
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.[1][3][7] As such, it shows a profile of low misuse liability.[7] Its actions are in contrast to modafinil and other analogues, which do significantly increase nucleus accumbens dopamine levels, albeit much less robustly than cocaine.[1] 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.[5][1][3][7] It has also been found to reduce methamphetamine self-administration and escalation of its intake.[1][3]
Preclinical development
JJC8-016 was under investigation for the potential treatment of PSUD.[7] However, it was abandoned following findings that it interacts with high affinity at the hERG antitarget (IC50 = 60 nM) and thereby would be predicted to produce cardiotoxicity.[2][5][8][9] This was also the reason for the abandonment of vanoxerine (GBR-12909), a structurally distinct atypical DRI that was in clinical trials for PSUD.[5][10] In addition to its hERG affinity, JJC8-016 was described as having poor metabolic and pharmacokinetic characteristics.[7] Subsequently, more selective modafinil-derived DAT blockers, like JJC8-088 and JJC8-091, were developed.[1][9] JJC8-088 has ~90-fold higher affinity for the DAT than JJC8-016 and ~2-fold lower affinity for the hERG.[9] Newer related modafinil analogues and DRIs with further reduced affinity for the hERG were also subsequently developed.[11]
JJC8-016 was first described in the scientific literature by 2014.[6][4] However, the actual compound itself was first mentioned in a patent that dates back to 1992.[12]
See also
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Curr Opin Pharmacol 56: 13–21. February 2021. doi:10.1016/j.coph.2020.07.007. PMID 32927246.
- ↑ 2.0 2.1 "New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders". Annu Rev Pharmacol Toxicol 61 (1): 609–628. January 2021. doi:10.1146/annurev-pharmtox-030220-124205. PMID 33411583.
- ↑ 3.0 3.1 3.2 3.3 3.4 "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Front Neurosci 15. 2021. doi:10.3389/fnins.2021.656475. PMID 34121988.
- ↑ 4.0 4.1 4.2 4.3 4.4 "The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic". Neuropsychopharmacology 42 (9): 1871–1883. August 2017. doi:10.1038/npp.2017.41. PMID 28266501.
- ↑ 5.0 5.1 5.2 5.3 5.4 "Discovery and Development of Monoamine Transporter Ligands". Drug Development in Psychiatry. Advances in Neurobiology. 30. Cham. 2023. 101–129. doi:10.1007/978-3-031-21054-9_4. ISBN 978-3-031-21053-2.
- ↑ 6.0 6.1 "Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinylacetamide (modafinil) analogues"]. J Med Chem 57 (3): 1000–1013. February 2014. doi:10.1021/jm401754x. PMID 24494745.
- ↑ 7.0 7.1 7.2 7.3 7.4 "Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine". Neuropharmacology 158: 107609. November 2019. doi:10.1016/j.neuropharm.2019.04.015. PMID 31009632.
- ↑ "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. March 2023. doi:10.1124/jpet.122.001363. 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.".
- ↑ 9.0 9.1 9.2 "Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach". J Chem Inf Model 61 (9): 4266–4279. September 2021. doi:10.1021/acs.jcim.1c00856. 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).".
- ↑ "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochem Pharmacol 75 (1): 2–16. January 2008. doi:10.1016/j.bcp.2007.08.007. PMID 17897630.
- ↑ "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. February 2024. doi:10.1021/acsptsci.3c00322. PMID 38357284.
- ↑ Patricia Caldirola, Raimund Mannhold, & Hendrik Timmerman, US5171752 (1992 to Organon NV).
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