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| Drug class | Atypical dopamine reuptake inhibitor |
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| Formula | C24H25F2NS |
| Molar mass | 397.53 g·mol−1 |
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JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) that was 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]
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]
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]
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]
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.
The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
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A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.
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Flmodafinil, also known as bisfluoromodafinil and lauflumide, is a wakefulness-promoting agent related to modafinil which has been developed for treatment of a variety of different medical conditions. These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease. Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic.
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RDS03-94, or RDS3-094, is an atypical dopamine reuptake inhibitor that was derived from the wakefulness-promoting agent modafinil.
JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.
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JJC8-089 is a dopamine reuptake inhibitor (DRI) that was derived from modafinil and is related to JJC8-016, JJC8-088, and JJC8-091. Its affinity (Ki) for the dopamine transporter (DAT) is 37.8 nM, for the norepinephrine transporter (NET) is 11,820 nM, for the serotonin transporter (SERT) is 6,800 nM, and for the sigma σ1 receptor is 2.24 nM. It also has significant affinity for several dopamine receptors. JJC8-089 has substantially higher affinity for the DAT than modafinil. The drug shows pro-motivational effects in animals. It was first described in the scientific literature by 2016.
{{cite book}}: |journal= ignored (help)CS1 maint: location missing publisher (link)However, JJC8-016 failed cardiac safety tests by exhibiting relatively high affinity at hERG channels; thus, this analog was abandoned from further development.
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).