Publications from the Medication Development Program.
Tanda, Gianluigi; Hersey, Melinda; Hempel, Briana; Xi, Zheng-Xiong; Newman, Amy Hauck
Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder Journal Article
In: Current Opinion in Pharmacology, vol. 56, pp. 13 - 21, 2021, ISSN: 1471-4892.
Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.
Mereu, Maddalena; Hiranita, Takato; Jordan, Chloe J; Chun, Lauren E; Lopez, Jessica P; Coggiano, Mark A; Quarterman, Juliana C; Bi, Guo-Hua; Keighron, Jacqueline D; Xi, Zheng-Xiong; Newman, Amy Hauck; Katz, Jonathan L; Tanda, Gianluigi
Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions Journal Article
In: Neuropsychopharmacology, vol. 45, no. 9, pp. 1518–1526, 2020, ISBN: 1740-634X.
Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as ``smart drugs''by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.
Galaj, Ewa; Newman, Amy Hauck; Xi, Zheng-Xiong
Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges Journal Article
In: Neuroscience & Biobehavioral Reviews, vol. 114, pp. 38 - 52, 2020, ISSN: 0149-7634.
Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the current national opioid crisis. Although several opioid-based pharmacotherapies are available (e.g., methadone, buprenorphine, naloxone), they show limited effectiveness in long-term relapse prevention. In response to the opioid crisis, the National Institute on Drug Abuse proposed a list of pharmacological targets of highest priority for medication development for the treatment of opioid use disorders (OUD). Among these are antagonists of dopamine D3 receptors (D3R). In this review, we first review recent progress in research of the dopamine hypothesis of opioid reward and abuse and then describe the rationale and recent development of D3R ligands for the treatment of OUD. Herein, an emphasis is placed on the effectiveness of newly developed D3R antagonists in the animal models of OUD. These new drug candidates may also potentiate the analgesic effects of clinically used opioids, making them attractive as adjunctive medications for pain management and treatment of OUD.
Yue, Kai; Tanda, Gianluigi; Katz, Jonathan L; Zanettini, Claudio
A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids Journal Article
In: Behavioural Pharmacology, vol. 31, no. 2&3, 2020, ISBN: 0955-8810.
Jordan, Chloe J; He, Yi; Bi, Guo-Hua; You, Zhi-Bing; Cao, Jianjing; Xi, Zheng-Xiong; Newman, Amy Hauck
(±)VK4-40, a novel dopamine D3 receptor partial agonist, attenuates cocaine reward and relapse in rodents Journal Article
In: British Journal of Pharmacology, vol. 177, no. 20, pp. 4796-4807, 2020.
Background and Purpose Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with up-regulated dopamine D3 receptor expression in the brain. Therefore, most D3-based medication development has focused on D3 antagonists. However, D3 antagonists do not attenuate cocaine intake under ``easy'' self-administration conditions, when response requirements are low. We evaluated a novel, highly selective and metabolically stable D3 partial agonist, ($pm$)VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking. Experimental Approach The impact of ($pm$)VK4-40 on cocaine intake and relapse was evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of ($pm$)VK4-40 and cocaine in the mesolimbic dopamine system in mice. Sucrose self-administration in rats and a conditioned place preference paradigm in mice were used to evaluate the abuse potential of ($pm$)VK4-40 alone and other unwanted effects. Key Results ($pm$)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. ($pm$)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. ($pm$)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D3 partial agonist also failed to alter oral sucrose self-administration. Conclusion and Implications The novel D3 partial agonist, ($pm$)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D3 partial agonists as putative treatments for cocaine use disorder.
Shaik, Anver Basha; Kumar, Vivek; Bonifazi, Alessandro; Guerrero, Adrian M; Cemaj, Sophie L; Gadiano, Alexandra; Lam, Jenny; Xi, Zheng-Xiong; Rais, Rana; Slusher, Barbara S; Newman, Amy Hauck
Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3 Receptor Antagonists and Partial Agonists Journal Article
In: Journal of Medicinal Chemistry, vol. 62, no. 20, pp. 9061–9077, 2019, ISBN: 0022-2623.
Dopamine D3 receptors (D3R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D3R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D3R binding affinity (Ki = 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D3R selectivity as well as drug-like features required for development as pharmacotherapeutics.
Newman, Amy Hauck; Cao, Jianjing; Keighron, Jacqueline D; Jordan, Chloe J; Bi, Guo-Hua; Liang, Ying; Abramyan, Ara M; Avelar, Alicia J; Tschumi, Christopher W; Beckstead, Michael J; Shi, Lei; Tanda, Gianluigi; Xi, Zheng-Xiong
Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders. Journal Article
In: Neuropsychopharmacology, vol. 44, no. 8, pp. 1435–1444, 2019, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.
Keighron, Jacqueline D; Quarterman, Juliana C; Cao, Jianjing; DeMarco, Emily M; Coggiano, Mark A; Gleaves, Apre; Slack, Rachel D; Zanettini, Claudio; Newman, Amy Hauck; Tanda, Gianluigi
Effects of (R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell Journal Article
In: ACS Chemical Neuroscience, vol. 10, no. 4, pp. 2012–2021, 2019.
Recent discoveries have improved our understanding of the physiological and pathological roles of the dopamine transporter (DAT); however, only a few drugs are clinically available for DAT-implicated disorders. Among those drugs, modafinil (MOD) and its (R)-enantiomer (R-MOD) have been used off-label as therapies for psychostimulant use disorders, but they have shown limited effectiveness in clinical trials. Recent preclinical studies on MOD and R-MOD have led to chemically modified structures aimed toward improving their neurobiological properties that might lead to more effective therapeutics for stimulant use disorders. This study examines three MOD analogues (JJC8-016, JJC8-088, and JJC8-091) with improved DAT affinities compared to their parent compound. These compounds were investigated for their effects on the neurochemistry (brain microdialysis and FSCV) and behavior (ambulatory activity) of male Swiss-Webster mice. Our data indicate that these compounds have dissimilar effects on tonic and phasic dopamine in the nucleus accumbens shell and variability in producing ambulatory activity. These results suggest that small changes in the chemical structure of a DAT inhibitor can cause compounds such as JJC8-088 to produce effects similar to abused psychostimulants like cocaine. In contrast, other compounds like JJC8-091 do not share cocaine-like effects and have a more atypical DAT-inhibitor profile, which may prove to be an advancement in the treatment of psychostimulant use disorders.
Lee, Mary R; Rohn, Matthew C H; Zanettini, Claudio; Coggiano, Mark A; Leggio, Lorenzo; Tanda, Gianluigi
Effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels Journal Article
In: Annals of the New York Academy of Sciences, vol. 1455, no. 1, pp. 173-184, 2019.
Abstract The neuropeptide oxytocin (OT) alters behaviors related to the administration of drugs of abuse, including stimulants. OT also plays a key role in social bonding, which involves an interaction between OT and dopamine (DA) in the nucleus accumbens (NAc). The nature of the interaction between OT and DA in the striatum in the context of psychostimulants is unclear. We investigated the effect of OT, delivered intraperitoneally, on the methylphenidate (MP) dose--response function for self-administration in rats. Food was used as a control condition. In a microdialysis study, we measured the effect of intraperitoneal OT on MP-stimulated striatal DA levels. Systemic OT pretreatment caused a downward shift in the MP dose--response function for self-administration, while having no effect on motor activity. OT also caused a reduction in food self-administration, although a significantly higher dose of OT was required for this effect compared with that required for a reduction of MP self-administration. Systemic OT pretreatment caused a potentiation of MP-stimulated DA levels in the NAc shell but not in the core. The significance of these findings is discussed, including the potential of OT as a therapeutic agent for addictive disorders.
Keighron, Jacqueline D; Giancola, JoLynn B; Shaffer, Rachel J; DeMarco, Emily M; Coggiano, Mark A; Slack, Rachel D; Newman, Amy Hauck; Tanda, Gianluigi
Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats Journal Article
In: European Journal of Neuroscience, vol. 50, no. 3, pp. 2045-2053, 2019.
Abstract Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure--activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (R)-enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast-scan cyclic voltammetry and by microdialysis in Sprague-Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1-048 and JBG1-049. The results show that (R)-modafinil (R-MOD), JBG1-048, and JBG1-049, when administered intravenously with cumulative drug-doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R-MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.