The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic

Abstract

(±)Modafinil ((±)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (±)MOD analogs, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters, and enzymes. Although at a concentration of 10 μM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D-like, and sigma receptors. R-MOD was more selective, but had much lower affinity at the DAT (K=3 μM) than JJC8-016 (K=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.

Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons

“…Like cocaine, (±)-modafinil is a stimulant (Young et al, 2011) and has been reported to have reinforcing properties in rhesus monkeys (Gold and Balster, 1996). Nevertheless, neither the racemate nor R-modafinil is self-administered in rodents and they do not exhibit abuse liability in humans, despite a mechanism of action that might predict this (Mereu et al 2013 and 2017, Volkow et al 2009; Zhang et al, 2017). …”

“…In contrast however, JHW 007 decreased IPSC amplitude in a manner consistent with D2 receptor antagonism. Unlike cocaine and R-modafinil (Zhang et al, 2017), JHW 007 has affinity for the D2L receptor (47.1 nM, Katz et al, 2004) and is a weak D2 receptor antagonist (IC 50 = 2 μM, Cao et al, 2016) in addition to exhibiting 12 nM binding affinity for DAT (Kopajtic et al, 2010). This could explain how mid-micromolar concentrations of JHW 007 reduced DA-mediated current amplitudes.…”

“…These effects are probably best described as occlusion and are what might be expected if cocaine itself was applied sequentially in two increasing concentrations. Indeed, although R-modafinil is not self-administered (Zhang et al, 2017) it does share other behavioral actions with cocaine in rodents (Loland et al, 2012). Notably, R-modafinil is not as effective in attenuating the self-administration of cocaine as JHW 007 or a recently reported modafinil analogue, JJC8-016 (Okunola-Bakare et al, 2014; Cao et al, 2016; Zhang et al, 2017).…”

“…Indeed, although R-modafinil is not self-administered (Zhang et al, 2017) it does share other behavioral actions with cocaine in rodents (Loland et al, 2012). Notably, R-modafinil is not as effective in attenuating the self-administration of cocaine as JHW 007 or a recently reported modafinil analogue, JJC8-016 (Okunola-Bakare et al, 2014; Cao et al, 2016; Zhang et al, 2017). In contrast, JHW 007 appeared to blunt the cellular effects of cocaine in a concentration-dependent manner that did not resemble occlusion.…”

“…These atypical agents are structurally diverse DAT inhibitors that include the benztropine analogue JHW 007 (Agoston et al, 1997) and the benzhydryl compound R-modafinil, the latter of which is currently approved by the FDA as both the R-isomer and the racemate to treat narcolepsy, sleep apnea, and shift-work sleep disorders. These compounds have less propensity than cocaine to increase locomotion or produce reinforcement in rodents (Cao et al, 2011; Desai et al, 2005; Li et al, 2013) and JHW 007 has been shown to reduce cocaine and methamphetamine self-administration (Hiranita et al, 2009; Li et al, 2013; Hiranita et al, 2014) whereas R-modafinil is less effective (Zhang et al, 2017). In contrast to cocaine, R-modafinil and JHW 007 prefer binding to an occluded conformation of DAT (Loland et al, 2008; Loland et al, 2012).…”