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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) 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] However, the actual compound itself was first mentioned in a patent that dates back to 1992. [12]
{{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).