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 D₂-like, and sigma₁ receptors. R-MOD was more selective, but had much lower affinity at the DAT (K_i=3 μM) than JJC8-016 (K_i=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.

Figure 1

Effects of R-MOD and JJC8-016 on cocaine or sucrose self-administration. (a) R-MOD (10, 30, and 100 mg/kg) had no effect on cocaine self-administration. (b) JJC8-016 (10 and 30 mg/kg) dose-dependently inhibited cocaine self-administration. (c) JJC8-016, at the same doses, also inhibited oral sucrose self-administration. (d) R-MOD (10 and 30 mg/kg) shifted the cocaine dose–response curve downward and inhibited cocaine self-administration maintained by low doses (0.0313 and 0.0625 mg/kg/infusion) of cocaine. (e) JJC8-016 (10 and 30 mg/kg) dose-dependently shifted the cocaine dose–response curve downward and inhibited cocaine self-administration maintained by a wide dose range of cocaine (0.0313, 0.0625, 0.125, and 0.25 mg/kg/infusion). *P<0.05, **p<0.01, and ***p<0.001 compared with vehicle.

Figure 2

Effects of R-MOD and JJC8-016 on basal and cocaine-enhanced locomotor activity. (a) Pretreatment with R-MOD did not significantly alter cocaine-enhanced locomotor activity. (b) Pretreatment with JJC8-016 dose-dependently attenuated cocaine-induced increase in locomotion. (c) R-MOD alone dose-dependently increased locomotor activity. (d) JJC8-016 did not significantly alter basal level of locomotor behavior. Within-subjects design, n=8 in each treatment. *P<0.05, **p<0.01, and ***p<0.001 compared with vehicle control.

Figure 3

Evaluation of the rewarding effects of R-modafinil and JJC8-016 in experimental animals. (a) Drug-naive rats rapidly acquired intravenous self-administration of cocaine, but not JJC8-016. JJC8-016 substitution for cocaine cannot maintain stable self-administration in rats previously experienced at self-administering cocaine, whereas cocaine substitution for JJC8-016 rapidly produced intravenous self-administration for cocaine in rats previously trained for JJC8-016 self-administration. (b) Systemic administration of JJC8-016, 10–30 mg/kg i.p., failed to alter extracellular dopamine (DA) in the nucleus accumbens. Results are means, with vertical bars representing SEM, of the amount of DA in 10 min dialysate samples, expressed as percentage of basal values. (c) Systemic administration of R-MOD dose-dependently decreased brain-stimulation reward (BSR) threshold (Θ₀), indicating enhanced brain reward. (d) Systemic administration of the same does of JJC8-016 had no effect on electrical BSR. *P<0.05, **p<0.01, and ***p<0.001 compared with the vehicle control group (c) or the basal levels of self-administration before the drug substitution test (a).

Figure 4

Effects of R-MOD and JJC8-016 on cocaine-primed reinstatement of cocaine-seeking behavior. (a, b) Active lever responses during the last session of cocaine self-administration, last session of extinction, and reinstatement testing illustrating that pretreatment with R-MOD (a) or JJC8-016 (b) dose-dependently inhibited cocaine-triggered reinstatement of drug-seeking behavior. A threefold higher dose (100 mg/kg) of R-MOD than JJC8-016 (30 mg/kg) is required to produce this inhibitory effect. (c, d) Active lever responses during the last session of cocaine self-administration, extinction, and reinstatement testing illustrating that R-MOD, at 100 mg/kg, induced reinstatement of cocaine-seeking behavior, whereas JJC8-016 did not at each drug dose (10 and 30 mg/kg). *P<0.05 and **p<0.001 compared with the vehicle control.