Publications from the Medication Development Program.
2017 |
Zhang, Hai-Ying; Bi, Guo-Hua; Yang, Hong-Ju; He, Yi; Xue, Gilbert; Cao, Jianjing; Tanda, Gianluigi; Gardner, Eliot L; Newman, Amy Hauck; Xi, Zheng-Xiong The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic. Journal Article In: Neuropsychopharmacology, vol. 42, no. 9, pp. 1871–1883, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Zhang:2017aa,(+/-)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 muM, 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 (Ki=3 muM) 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. |
2016 |
Cao, Jianjing; Slack, Rachel D; Bakare, Oluyomi M; Burzynski, Caitlin; Rais, Rana; Slusher, Barbara S; Kopajtic, Theresa; Bonifazi, Alessandro; Ellenberger, Michael P; Yano, Hideaki; He, Yi; Bi, Guo-Hua; Xi, Zheng-Xiong; Loland, Claus J; Newman, Amy Hauck Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors. Journal Article In: J Med Chem, vol. 59, no. 23, pp. 10676–10691, 2016, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @article{Cao2016,The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication. |
Lee, Mary R; Rohn, Matthew C H; Tanda, Gianluigi; Leggio, Lorenzo Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date. Journal Article In: CNS Drugs, vol. 30, no. 2, pp. 109–123, 2016, ISSN: 1179-1934 (Electronic); 1172-7047 (Linking). @article{Lee2016,The neuropeptide oxytocin plays a role in reward, stress, social affiliation, learning, and memory processes. As such, there is increasing interest in oxytocin as a potential treatment for addictions. The endogenous oxytocin system is itself altered by short- or long-term exposure to drugs of abuse. A large number of preclinical studies in rodents have investigated the effect of oxytocin administration on various drug-induced behaviors to determine whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, the mechanisms by which oxytocin acts to modify the behavioral response to drugs of abuse are beginning to be understood. More recently, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependence. This review summarizes the preclinical as well as clinical literature to date on the oxytocin system and its relevance to drug and alcohol addiction. |
2015 |
Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi; Yang, Hong-Ju; Gao, Jun-Tao; Okunola-Bakare, Oluyomi M; Slack, Rachel D; Gardner, Eliot L; Xi, Zheng-Xiong; Newman, Amy Hauck R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats Journal Article In: Neuropsychopharmacology, vol. 40, no. 7, pp. 1762–1771, 2015, ISBN: 1740-634X. @article{Wang:2015aab,($pm$)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of ($pm$)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long--Evans rats. As Long--Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long--Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans. |
