title: 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 sigma1receptors. R-MOD was more selective, but had much lower affinity at the DAT (Ki=3 μM) than JJC8-016 (Ki=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.
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Xue
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.affiliation: Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Amy Hauck
authors.identifier: http://orcid.org/0000-0002-4812-9474
authors.initials: AH
authors.lastname: Newman
authors.affiliation: Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.|Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Zheng-Xiong
authors.identifier: http://orcid.org/0000-0001-6482-8104
authors.initials: ZX
authors.lastname: Xi
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D020318:Rats, Long-Evans; D012201:Reward; D012646:Self Administration
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C000626988:N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine; D011437:Propylamines; D003042:Cocaine; D004298:Dopamine