vanoxerine (GBR 12909) / Laguna Pharma - LARVOL DELTA

Insight into the differential binding mechanisms of substrate, cocaine, and therapeutic drugs with dopamine transporter based on molecular dynamics simulations. (PubMed, Int J Biol Macromol) - "Here, all-atom molecular dynamics (MD) simulations combined with MM/PBSA calculations, principal component analysis (PCA), and free energy landscape (FEL) analysis were employed to compare the binding modes of dopamine (DA), cocaine, Benztropine (BZT), and GBR12909 (GBR) to DAT. Gate distance, PCA, and FEL analyses further revealed ligand-dependent gating regulation: BZT imposes the strongest conformational constraint, cocaine stabilizes the outward-open state, GBR seals the extracellular entrance with intracellular gate transition, and DA preserves conformational tunability. These findings provide a systematic atomic-level mechanistic framework for understanding DAT differential regulation and guiding the development of novel competitive inhibitors."

Journal

GBR 12909, a Selective Dopamine Transporter Inhibitor, Differentially Modulates Affective, Exploratory and Cognitive Domains in Zebrafish. (PubMed, Eur J Neurosci) - "These data reflect affective and cognitive disturbances consistent with dopaminergic overstimulation that triggers manic- and depressive-like phenotypes, thereby recapitulating behavioural phenotypes relevant to multiple domains affected in BD. Collectively, our findings support that GBR12909 elicits dopaminergic-driven behavioural phenotypes relevant to multiple domains of BD, providing a translational model for studying the neurobiological bases of DAT inhibition across distinct behavioural domains."

Journal • Bipolar Disorder • CNS Disorders • Cognitive Disorders • Depression • Mood Disorders • Psychiatry

Molecular basis for the dopamine reuptake and inhibition mechanism of human dopamine transporter. (PubMed, Structure) - "The antidepressant compounds bupropion and vanoxerine bind to the central site of hDAT and inhibit substrate transport. Our findings reveal the molecular mechanisms governing DA reuptake and the specific ways in which hDAT interacts with antidepressant compounds. These insights provide a structural basis for the design of therapeutic agents targeting hDAT."

Journal • CNS Disorders • Depression • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Glutathione deficiency in the early postnatal developmental period as a neurodevelopmental animal model of schizophrenia. (PubMed, Pharmacol Rep) - "Hence, administration of the GSH synthesis inhibitor L-buthionine-(S, R)-sulfoximine (BSO) alone and in co-treatment with the dopamine reuptake inhibitor 1-[2-[Bis-4(fluorophenyl)methoxy]ethyl]-4-3-(3-phenylpropyl) (GBR 12909) to rodents in neonatal period produces good neurodevelopmental models offering an opportunity to examine various neuroanatomical changes and different symptoms in schizophrenia spectrum...Such artificially induced dysfunctions, discussed in this article, suggest the usefulness of these neurodevelopmental models in research on the pathomechanisms of schizophrenia. The aim of this review is to analyze the literature on the impact of GSH deficiency on the etiopathology of schizophrenia, with particular emphasis on neurodevelopmental animal models in which oxidative stress during early postnatal development causes schizophrenia-like symptoms in adulthood."

Journal • Preclinical • Review • CNS Disorders • Psychiatry • Schizophrenia • Vascular Neurology

Sex-dependent disruption of affective behaviors by GBR 12909: relevance to bipolar disorders. (PubMed, Neuropharmacology) - "GBR abolished preference for the emotional target only in males, suggesting altered emotion recognition. This work introduces new phenotypic dimensions relevant to study BD and highlights the necessity to study both sexes which are not strictly equivalent in their behavioral responses."

Journal • Bipolar Disorder • CNS Disorders • Immunology • Mood Disorders • Psychiatry

Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions. (PubMed, Nat Aging) - "We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration, and propose these compounds as neuroprotective interventions. Furthermore, we identify neurotoxins that accelerate neurodegeneration, indicating that distinguishing aging trajectories between neuron types can inform on protective interventions as well as risk factors."

Journal • CNS Disorders

Reassessing the Conduct of Patch Clamp Cardiac Ion Channel Assays to Improve Nonclinical Data Translation to Clinical ECG Changes and Proarrythmia Risk. (PubMed, Clin Transl Sci) - "Finally, astemizole, risperidone, and clarithromycin-"intermediate TdP risk" CiPA drugs-were reported to have hERG-active metabolites, yet hERG data for metabolites were not integrated when developing in silico human myocyte models for risk prediction...Here the effects of chloroquine, lopinavir, ritonavir, and vanoxerine on hERG, CaV1.2, and/or NaV1.5 channels were studied using protocols consistent with ICH S7B Q&A 2.1 best practices...The results showed improved alignment between ion channel block profiles and drug-induced ECG changes and proarrhythmia, underscoring the importance of using physiologically relevant experimental protocols, accounting for ion channel-active metabolites, and continuing to build the knowledge base of arrhythmogenesis mechanisms. Data may be found at: https://osf.io/7rfua/."

Journal • Cardiovascular • NAV1

Effect of morphine dependence and withdrawal on operant social interaction in male and female rats. (PubMed, Drug Alcohol Depend) - "Based on the literature, we also tested if a kappa opioid receptor (KOR) antagonist (LY2456302) and serotonin and dopamine reuptake inhibitors (fluoxetine and GBR12909), would independently reverse the effect of morphine exposure on social self-administration. Opioid dependence, but not withdrawal, decreased operant social interaction and food self-administration in male and female rats. This effect appears independent of KOR, serotonin, or dopamine signaling."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Glutathione deficiency and disturbances of sulfur homeostasis in the pathophysiology of schizophrenia (PubMed, Postepy Biochem) - "In one of the recently developed rat’s neurodevelopmental model, schizophrenic-like changes were induced by administration of buthioninesulfoximine (BSO) - an inhibitor of glutathione synthesis and a dopamine reuptake inhibitor - the compound GBR 12909 during the developmental period...The usefulness of the developed model was tested by the effect of the antipsychotic drug aripiprazole and N-acetylcysteine...At the biochemical level, both drugs significantly reduced the elevated concentration of bound sulfane sulfur in the hippocampus of model rats. Recent studies indicate that in the neurodevelopmental pathophysiology of schizophrenia, disturbances in the homeostasis of sulfur compounds play an important role, which are corrected by the action of drugs."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Unveiling conformation-selective regulation of the norepinephrine transporter. (PubMed, Cell) - "Through cryo-electron microscopy analysis of NET complexes with levomilnacipran, vanoxerine, and vilazodone, we identify a previously undefined allosteric site within NET's inner vestibule that enables conformation-selective regulation. Moreover, our structural identification of inhibitor occupancy at this conformation-selective site defines a mechanistic framework for targeted therapeutic intervention. These findings advance our understanding of NET allosteric modulation, providing a structure-guided framework for developing next-generation antidepressants targeting the inward-open conformation of NET for the treatment of neuropsychiatric disorders."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Psychiatry

Assessing adult zebrafish despair-like behaviors in the small vertical cylinder immobility test (VCIT). (PubMed, J Neurosci Methods) - "VCIT is sensitive to various stress-related manipulations and their bidirectional pharmacological modulation, hence emphasizing the growing relevance and potential of zebrafish in advancing neuropsychiatric research and identifying innovative treatments for neuropsychiatric disorders."

Journal • CNS Disorders • Depression • Mental Retardation • Psychiatry

Nonclinical Human Cardiac New Approach Methodologies (NAMs) Predict Vanoxerine-Induced Proarrhythmic Potential. (PubMed, J Cardiovasc Dev Dis) - "These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies."

Journal • Cardiovascular

N-acetylcysteine enhances the antipsychotic effect of aripiprazole in the neurodevelopmental rat model of schizophrenia. (PubMed, Pharmacol Biochem Behav) - "The schizophrenia-like behavior was induced in Sprague-Dawley male pups in the neonatal days p5-p16 by repeated administration of the glutathione synthesis inhibitor L-butionine-(S,R)-sulfoximine (BSO) given together with the dopamine reuptake inhibitor 1-[2-[Bis-4(fluorophenyl)methoxy]ethyl]-4-3-(3-phenylpropyl) (GBR 12909)...Moreover, repeated co-treatment with low doses of ARI with NAC also reversed schizophrenia-like behavior in the neurodevelopmental rat model of schizophrenia. The above results indicated that NAC enhanced the action of ARI in the used neurodevelopmental rat model of schizophrenia, and the mechanism of action of the used drugs in this model is discussed."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Hippocampal long-term potentiation is modulated by exercise-induced alterations in dopaminergic synaptic transmission in mice selectively bred for high voluntary wheel running. (PubMed, Restor Neurol Neurosci) - "The increased hippocampal LTP seen in HR mice with wheel access may be related to alterations in dopaminergic synaptic transmission that underlie the neurophysiological basis of hyperactivity, motor disorders, and/or motivation."

Journal • Preclinical • CNS Disorders

The dopamine transporter inhibition using GBR 12909 as a novel pharmacological tool to assess bipolar disorder-like neurobehavioral phenotypes in zebrafish. (PubMed, Behav Brain Res) - "We also emphasize the well-conserved DA-mediated signaling in zebrafish and the early expression of dopaminergic biomarkers in the brain, especially focusing on dopamine transporter (DAT), the main target of GBR 12909. Finally, we discuss potential advantages and limitations in the field, the perspectives of using GBR 12909 in BD research, and how distinct validation criteria (i.e., face, predictive, and construct validity) can be assessed in translational approaches using zebrafish-based models."

Journal • Review • Bipolar Disorder • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry

Exploration of vanoxerine analogues as antibacterial agents. (PubMed, J Antibiot (Tokyo)) - "The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Dopamine reuptake and inhibitory mechanisms in human dopamine transporter. (PubMed, Nature) - "Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature. (PubMed, Br J Pharmacol) - "We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target."

Journal • Immunology • Neuralgia • Oncology • Pain • TRPM8 • TRPV1

Repurposing the dopamine transporter antagonist vanoxerine to treat colorectal cancer. (PubMed, Nat Cancer) - No abstract available

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors. (PubMed, Nat Cancer) - "Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors."

Cancer stem • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

The influence of acute dopamine transporter inhibition on manic-, depressive-like phenotypes and brain oxidative status in adult zebrafish. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Depending on the dose, GBR 12909 also decreased SOD activity and TBARS levels, as well as increased GR activity and NPSH content. Collectively, our novel findings show that a single GBR 12909 administration evokes neurobehavioral changes that recapitulate manic- and depressive-like states observed in rodents, fostering the use of zebrafish models to explore BD-like responses in translational neuroscience research."

Journal • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Cortical and Striatal Astrocytes of Neonatal Rats Display Distinct Molecular and Pharmacological Characteristics of Dopamine Uptake. (PubMed, Int J Mol Sci) - "The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse."

Journal • Preclinical

Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder. (PubMed, J Pharmacol Sci) - "Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP...GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo...Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD."

Journal • Preclinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Cardiovascular • CNS Disorders • Mental Retardation • Psychiatry

Development and validation of an automated microfluidic perfusion platform for parallelized screening of compounds in vitro. (PubMed, Basic Clin Pharmacol Toxicol) - "The platform was able to produce the expected releasing (D-Amphetamine, p-Chloroamphetamine) or inhibiting (GBR12909, paroxetine) profiles for the two transporters. Reduction of manual operation and introduction of automated flow control enabled the implementation of stronger standardized protocols and the possibility to obtain higher throughput by increasing parallelization."

Journal • Preclinical • Behavior Disorders • Psychiatry

Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters. (PubMed, Biomedicines) - "Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur."

Combination therapy • Journal