ZL-006 / Indiana University, Anagin - LARVOL DELTA

Effects of different SSRIs on nNOS mRNA expression in the hippocampus and prefrontal cortex of chronically stressed rats. (PubMed, Neuropsychobiology) - "After the addition of the PSD-95/nNOS inhibitor ZL006, nNOS levels decreased significantly in the paroxetine group but did not significantly change in the citalopram group. The mechanisms involved in nNOS expression differed between the paroxetine and citalopram groups. Paroxetine-induced nNOS expression may be related to PSD-95/nNOS."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry

Unveiling the role of PSD95 phosphorylation after traumatic brain injury: insights from phosphoproteomic analysis. (PubMed, BMC Neurol) - "After TBI, PSD95 was significantly phosphorylated at Ser417 and Ser418. ZL006 markedly reduced brain lesion volume and apoptotic rate and suppressed the phosphorylation of PSD95 at Ser418."

Journal • CNS Disorders • Vascular Neurology • DLG4

Uncoupling toxic NO signaling: Progress, challenges, and therapeutic promise of disrupting the PSD-95/nNOS protein-protein interaction. (PubMed, Eur J Med Chem) - "Over the past two decades, cell-penetrant peptides such as nerinetide (Tat-NR2B9c) have validated the target from rodent stroke models to phase-III clinical trials, while bivalent constructs achieve low-nanomolar affinity and extended brain exposure. Parallel medicinal-chemistry campaigns have delivered multiple small-molecule scaffolds (IC87201, ZL006, SCR-4026, PCC-0105002) that cross the blood-brain barrier, disrupt the complex at low-micromolar concentrations, and demonstrate efficacy in ischemic stroke, neuropathic pain, and neuropsychiatric paradigms without the liabilities of NMDAR antagonists...Structural elucidation of ligand-bound complexes, covalent and bivalent chemistries, and AI-guided design promise to surmount these hurdles. Collectively, the evidence positions PSD-95/nNOS disruption as a versatile, clinically achievable approach for mitigating excitotoxic and nociceptive pathology and sets the stage for first-in-class therapies that uncouple toxic NO..."

Journal • Review • Cardiovascular • Ischemic stroke • Neuralgia • Pain • Psychiatry

Metabolite classification through novel metabolomics framework reveals mechanism underlying the therapeutic effects of PSD95-nNOS blockade for post-stroke depression. (PubMed, Metabolomics) - "This novel metabolomics strategy, by discriminating between treatment-associated and compound-intrinsic pathways, provided unprecedented mechanistic insights into ZL006's therapeutic effects. The findings suggest that ZL006 alleviates PSD through coordinated modulation of neuroplasticity, angiogenesis, and stress responses via PSD95-nNOS targeting. This integrated analytical approach presents a valuable framework for mechanistic investigation of therapeutic compounds."

Journal • Cardiovascular • CNS Disorders • Depression • Mood Disorders • Psychiatry • DLG4

Anti-neuroinflammatory agent rhein lysinate-based self-assembled injectable hydrogel loaded with ZL006 for promoting post-stroke functional recovery. (PubMed, Biomaterials) - "The RHL gel can be loaded with the bioactive agents such as 5-Fluorouracil, temozolomide, edaravone, and ZL006, mainly based on efficient stacking between aromatic rings in the bioactive agents and anthraquinone rings in the hydrogel network structure. When a single dose of ZL006-RHL gel is administrated to stroke cavity in the subacute phase of stroke, RHL gel matrix effectively reduces post-stroke neuroinflammation, creates a favorable environment for ZL006 to enhance neuroplasticity, and confers a sustained and stable action to ZL006, leading to a long-lasting improvement of motor performance. This study may provide a valuable strategy for therapeutic intervention to promote post-stroke functional recovery, for which there are no clinically available drugs."

Journal • Cardiovascular • Inflammation

Combinatorial therapy with sub-effective Ro25-6981 and ZL006 ameliorates depressive-like behavior in single or combined stressed male mice. (PubMed, Biochem Biophys Res Commun) - "Moreover, the combinatorial treatment had negligible effects on object memory and contextual fear memory. Our data establish a combined therapy paradigm, providing a potential strategy targeting major depression."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Psychiatry • DLG4 • GRIN2B

Reduction of Oxidative Stress and Excitotoxicity by Mesenchymal Stem Cell Biomimetic Co-Delivery System for Cerebral Ischemia-Reperfusion Injury Treatment. (PubMed, Small) - "In this study, a multifunctional nanoplatform (designated as PB-006@MSC) is developed using ZL006-loaded Prussian blue nanoparticles (PBNPs) camouflaged by a mesenchymal stem cell (MSC) membrane (MSCm)...In animal experiments, PB-006@MSC integrated reactive oxygen species (ROS) scavenging and neuroprotection. Thereby, it selectively targeted the cerebral ischemic penumbra (about fourfold higher accumulation at 24 h than in the non-targeted group), demonstrated a remarkable therapeutic efficacy in reducing the volume of cerebral infarction (from 37.1% to 2.3%), protected the neurogenic functions, and ameliorated the mortality."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Reperfusion Injury

ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala. (PubMed, Cereb Cortex) - "Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons."

Journal • CNS Disorders • Psychiatry • Vascular Neurology

Preclinical evaluation of ZL006-05, a new antistroke drug with fast-onset antidepressant and anxiolytic effects. (PubMed, Stroke Vasc Neurol) - "ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy, safety and targeting of clinical issues."

Journal • Preclinical • Cardiovascular • CNS Disorders • Depression • Ischemic stroke • Pain • Psychiatry

Enhanced AMPAR-dependent synaptic transmission by S-nitrosylation in the vmPFC contributes to chronic inflammatory pain-induced persistent anxiety in mice. (PubMed, Acta Pharmacol Sin) - "Moreover, administration of ZL006, a small molecular inhibitor disrupting the interaction of nNOS and PSD-95 (20 mg·kg·d, for 5 days, i.p.), significantly reduced nitric oxide production and S-nitrosylation of AMPAR-interacting proteins in the vmPFC, resulting in anxiolytic-like effects in anxious mice after ibuprofen treatment. We conclude that S-nitrosylation is necessary for AMPAR trafficking and function in the vmPFC under chronic inflammatory pain-induced persistent anxiety conditions, and nNOS-PSD-95 inhibitors could be potential anxiolytics specific for chronic inflammatory pain-induced persistent anxiety after analgesic treatment."

Journal • Preclinical • CNS Disorders • Mood Disorders • Pain • Psychiatry

Humanized cerebral organoids-based ischemic stroke model for discovering of potential anti-stroke agents. (PubMed, Acta Pharmacol Sin) - "The sensitivity of the model to ischemic injury and related treatment was validated by the proven pan-Caspase inhibitor Z-VAD-FMK (20 μM) and Bcl-2 inhibitor navitoclax (0.5 μM). Neuroprotective agents edaravone, butylphthalide, P7C3-A20 and ZL006 (10 μM for each) exerted similar beneficial effects in this model. Taken together, this study establishes a humanized ischemic stroke model based on COs, and provides evidence as a new research platform for anti-stroke drug development."

Journal • Cardiovascular • Ischemic stroke

Inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse vulnerability in rats. (PubMed, Addict Biol) - "We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self-administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse-like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction."

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

An Injectable Hydrogel for Treatment of Chronic Neuropathic Pain. (PubMed, Macromol Biosci) - "A small-molecular compound ZL006 can suppress N-Methyl-D-aspartate receptor (NMDAR)-mediated neuropathic pain behaviors without blocking essential NMDAR function and brings new hope for neuropathic pain therapy...The thermo-responsive hydrogel at body temperature enables the extended release of encapsulated ZL006, and therefore a single subcutaneous injection of ZL006-hydrogel produces a prolonged and stable analgesic action in mice with spinal nerve ligation. Our study provides a practical chronic neuropathic pain therapy and a new perspective on future applications of ZL006."

Journal • Neuralgia • Pain

Inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse vulnerability in rats (Neuroscience 2021) - "We used a conditioned place preference approach to evaluate the impact of two small-molecule PSD95-nNOS inhibitors ˗ IC87201 and ZL006 ˗ on the rewarding effects of morphine. Our results provide behavioral and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse without producing abuse liability on its own. Our studies highlight a previously unrecognized role for the use of PSD95-nNOS disruptors as a novel non-narcotic therapeutic strategy that shows promise for treating opioid addiction.; Grant Support: NIH/NIDA DA042584 to AGH and GVR"

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

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA Receptor. (PubMed, Neurotherapeutics) - "Mechanistically, intravenous injection of ZL006-05 potentiated the GABA receptor agonist-evoked currents in the neurons of the dorsal horn and anterior cingulate cortex and also blocked the paclitaxel-induced increase in postsynaptic density-95-neuronal nitric oxide synthase interaction in dorsal horn. Our findings strongly suggest that ZL006-05 may be a new candidate for the management of cancer pain and chemotherapy-induced peripheral neuropathic pain."

Journal • Musculoskeletal Pain • Neuralgia • Oncology • Osteosarcoma • Pain • Peripheral Neuropathic Pain • Sarcoma • Solid Tumor

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice. (PubMed, Psychopharmacology (Berl)) - "Our study highlights the importance of the PSD95/nNOS pathway in mediating SI-induced escalation of attack behavior. ZL006 may be a promising therapeutic strategy for treating aggressive behaviors."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease

A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABARs. (PubMed, Theranostics) - " By targeting nNOS-PSD-95 interaction and α2-containing GABAR simultaneously, chronic use of ZL006-05 can avoid analgesic tolerance and unwanted side effects. Therefore, we offer a novel candidate drug without analgesic tolerance for treating neuropathic pain."

Journal • Neuralgia • Pain • Peripheral Neuropathic Pain • BDNF

Uncoupling nNOS-PSD-95 in mPFC inhibits morphine priming-induced reinstatement after extinction training. (PubMed, Biochem Biophys Res Commun) - "Moreover, effects of ZL006 on the reinstatement of morphine CPP and CREB activation depended on nNOS-PSD-95 target. Together, our findings suggest that nNOS-PSD-95 in the mPFC contributes to reinstatement of morphine CPP, possibly through CREB dysfunction, offering a potential target to prevent relapse of drug abuse."

Journal

Neuroprotective effects of ZL006 in Aβ-treated neuronal cells. (PubMed, Neural Regen Res) - "ZL006 inhibited N2a cell death and oxidative stress induced by Aβ, while inhibition of Akt or Nrf2 abolished the protective effect of ZL006. These results demonstrated that ZL006 reduced Aβ-induced neuronal damage and oxidative stress, and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Ischemic stroke • Neuroblastoma • Oncology • Reperfusion Injury • Solid Tumor • HMOX1 • NFE2L2

Role of PSD95 and nNOS Interaction in Gene Regulation following Fear Conditioning and Implications for Molecular Mechanisms Underlying Post-Traumatic Stress Disorder (SOBP 2020) - " We show that fear conditioning enhances the PSD95-nNOS interaction and that the small-molecule ZL006 inhibits this interaction (p<0.05) (n=5 per group)... Our results reveal novel genetic targets that underlie plasticity of fear-memory circuitry via their contribution of NMDAR-mediated fear consolidation and can inform future strategies for targeting fear related disorders like PTSD. Funding Source: NIMH, NIH, NCATS"

CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

NMDA receptor modulation of glutamate release in activated neutrophils. (PubMed, EBioMedicine) - "These data suggest that release of glutamate by activated neutrophils augments ROS production in an autocrine manner via actions on NMDAR expressed by these cells. FUND: GLA: Academy Medical Sciences/Health Foundation Clinician Scientist. AVG is a Wellcome Trust Senior Research Fellow."

Journal

Disrupting nNOS-PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury. (PubMed, Cereb Cortex) - "Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS-PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling."

IO Biomarker • Journal