ifenprodil tartrate / Chiba University Hospital - LARVOL DELTA

Intracerebral ifenprodil enhances autophagy function in 6-OHDA-lesioned rats to provide synaptic plasticity. (PubMed, Folia Neuropathol) - "A notable improvement was observed in the CPU group. Our study showed that direct delivery of ifenprodil to specific brain regions produced superior therapeutic effects compared to systemic administration in 6-OHDA-lesioned rat models."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • BECN1 • DLG4 • PARP1

3-Substituted derivatives of 7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol generate radioligands for imaging brain GluN2B in vivo (ACS-Fall 2026) - "Binding affinity was evaluated in rat brain homogenate competition assays versus [3H]ifenprodil and screened through the NIMH Psychoactive Drug Screening Program... These studies define key structural determinants for high-affinity GluN2B binding. [11C]L3 and [11C]L6 demonstrate favorable in vivo characteristics, supporting further GluN2B-selective PET radioligand development for clinical imaging."

Preclinical • Alzheimer's Disease • CNS Disorders • GRIN2B

Acute Ethanol Exposure Inhibits GABA Uptake in Embryonic Chicken Retina. (PubMed, Neurochem Res) - "In contrast, Ifenprodil treatment did not alter the inhibitory effect of EtOH on GABA uptake, suggesting that GluN2B-containing NMDA receptors are not major contributors to this response...Acute exposure to 0.1% EtOH did not significantly alter GABA uptake at E16 as was indicated in E11, suggesting an age-dependent effect of EtOH on retinal development, independent of cell death. These results support the hypothesis that acute EtOH exposure modulates GABA transport during retinal development, with the involvement of PKA and PKC pathways in this response."

Journal • GRIN2B

Negative allosteric modulation of NMDA receptors with GluN2B subunit: synthesis of γ-amino alcohols embedded in a 1-benzoxepine scaffold. (PubMed, RSC Med Chem) - "Novel ligands for the ifenprodil binding site of NMDA receptors with GluN2B subunit were designed, synthesized and pharmacologically evaluated...Binding at human serum albumin correlated with the lipophilicity (e.g., 13b: PPB = 81%). Most of the 1-benzoxepines showed more than 65% metabolic stability during incubation with mouse liver microsomes and NADPH for 90 min."

Journal • GRIN2B

Potentiation effects of the positive allosteric modulator PTC-174 on NMDA receptors in neonatal male rat substantia nigra dopaminergic neurons. (PubMed, Br J Pharmacol) - "The main implication of the results in this paper is that PAMs like PTC-174 have the potential to enhance NMDA receptor signalling at substantia nigra dopaminergic neurons in vivo and so could enhance basal ganglia dopamine signalling."

Journal • Preclinical • GRIN2B

DNMT3a-mediated GluN2B desilencing in the anterior cingulate cortex underlies chemotherapy-induced neuropathic pain. (PubMed, Neuropharmacology) - "In a mouse model of paclitaxel (PTX)-induced CINP, we found that PTX downregulated DNA methyltransferase 3a (DNMT3a) in the ACC and induced mechanical and thermal pain hypersensitivity. Furthermore, intra-ACC application of the GluN2B antagonist Ifenprodil reversed pain hypersensitivity induced by either PTX or DNMT3a knockdown. Finally, our results establish DNMT3a-mediated epigenetic desilencing of GluN2B in the ACC as a key mechanism underlying PTX-induced neuropathic pain, identifying both as promising therapeutic targets for CINP."

Journal • Immunology • Neuralgia • Pain • DNMT3A • GRIN2A • GRIN2B

S-ketamine, but not R-ketamine, increases the spontaneous firing rate and the AMPA-evoked response of pyramidal neurons in the rat prefrontal cortex (CINP 2026) - "Although both R-ketamine and ifenprodil were shown to have an antidepressant-like effect in the forced swim test [Zhang et al, 2014; Poleszak et al, 2013], they do not increase AMPA-induced response in the mPFC, unlike racemic ketamine and S-ketamine that do both. The increase in AMPA-induced response may thus constitute a common factor underlying the antidepressant effects of ketamine and S-ketamine confirmed in the clinic. Such an increase in AMPA responsiveness coincides with an enhancement in expression of GluA1 subunit of AMPA receptors in the rat PFC by racemic ketamine [Piva et al, 2021]."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • GRIN2B

Systematic Identification of Therapeutic Targets and Repurposed Drugs for Stroke: From Genome Causal Analysis to Multilevel Validation. (PubMed, J Am Heart Assoc) - "This study established a potential causal link between GGCX and stroke risk, particularly ischemic stroke. GGCX represents a promising therapeutic target for ischemic stroke. Targeted GGCX expression upregulation and drug repurposing, particularly ifenprodil, may offer novel therapeutic avenues. Further validation is warranted to assess clinical efficacy and safety."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology

NMDA receptor mediated tonic excitatory currents are elicited by EAAT inhibition on human neocortical pyramidal neurons. (PubMed, Front Synaptic Neurosci) - "The tonic current was only partially reverted by the GluN2B subunit specific NMDA receptor (NMDAR) antagonist ifenprodil, whereas SICs were almost fully eliminated. The amplitude of the current was inversely proportional with the age of the patient and disappeared in elderly over the age of 70...In summary, NMDAR-dependent tonic inward currents are overlapping but partially separable phenomena from SICs. One might hypothesize that the tonic current is only present under excitotoxic conditions and do not determine physiological neuronal excitability in human."

Journal • Brain Cancer • Oncology • Solid Tumor • GRIN2B

β-Asarone, Tenuifolin, and YuanZhi Decoction Restore Cognitive Function and Modulate GRIN2B-Associated Autophagy in Alzheimer's Disease. (PubMed, Neurochem Res) - "Behavioral tests (MWM and NOR), Nissl staining, IHC, network pharmacology, molecular docking (including the GRIN2B inhibitor ifenprodil as positive control), Western blotting, biochemical assays, and RT-qPCR were performed...These abnormalities were significantly reversed by all treatments, with the combination and YuanZhi decoction showing greater efficacy. β-asarone, tenuifolin, their combination, and YuanZhi decoction alleviate GRIN2B-linked autophagic imbalance and mitochondrial stress in AD-like mice, supporting their therapeutic potential."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • GRIN2B • MAP1LC3A • SOD2

Increase of the AMPA-evoked response of pyramidal neurons in the rat medial prefrontal cortex following acute administration of ketamine and S-ketamine, but not R-ketamine. (PubMed, Int J Neuropsychopharmacol) - "An increase in the AMPA-induced response appears to constitute a common factor underlying the antidepressant-like effects of ketamine and S-ketamine. This increase did not correlate with change in mPFC pyramidal neurons firing activity."

Journal • Preclinical • Anesthesia • GRIN2B

Discovery and Evaluation of N-Arylindole-Based GluN2B-NMDAR Antagonists with Reduced Cardiotoxicity for the Treatment of Ischemic Stroke. (PubMed, J Med Chem) - "Molecular docking revealed its binding to the Ifenprodil site, partial overlap with EVT-101, and unique interactions. Molecular dynamics simulations confirmed stable receptor binding. Notably, NFI23 exhibited negligible hERG channel inhibition and excellent selectivity over other subtypes and σ1/σ2 receptors, supporting it as a promising and safer therapeutic candidate for ischemic stroke."

Journal • Cardiovascular • Ischemic stroke • GRIN2B

Differential effects of GluN2A and GluN2B subunits in the medial prefrontal cortex on chronic pain and anxiety/depressive-like behaviors (PubMed, Sheng Li Xue Bao) - "GluN2A antagonist (PEAQX) and GluN2B antagonist (Ifenprodil) were microinjected into the mPFC to observe their behavioral effects and underlying molecular mechanisms...Taken together, our findings suggest that GluN2A and GluN2B subunits in the mPFC differentially contribute to chronic pain and anxiety/depressive-like behaviors through their respective intracellular signaling. This study provides novel insights into the mechanisms underlying chronic pain and emotional comorbidity, and offers experimental evidence for developing targeted therapeutic strategies against specific NMDAR subunits."

Journal • CNS Disorders • Depression • Neuralgia • Pain • Psychiatry • GRIN2A • GRIN2B

Development of a MS binding assay to analyze the interactions of drugs with the ifenprodil binding site of NMDA receptors with GluN2B subunit. (PubMed, J Pharm Biomed Anal) - "Under optimized assay conditions, the MS binding assay provided a Kd value for the marker ifenprodil (Kd = 11 nM), which is comparable with the Kd value obtained in the radioligand binding assay for [3H]ifenprodil (Kd = 7.6 nM). Although the MS binding assay led to higher Ki values for known NMDA receptor antagonists, both assays showed the same trend of Ki values for these inhibitors."

Journal • CNS Disorders • Psychiatry • GRIN2B

Mice carrying a GluN2B protein-truncating variant have altered NMDA receptor subunit composition and their behavior recapitulates patient phenotypes. (PubMed, Cell Mol Life Sci) - "Electrophysiology in hippocampal neurons demonstrated reduced NMDA-induced currents, diminished ifenprodil sensitivity, and accelerated NMDAR-mediated EPSC deactivation, consistent with a shift toward GluN2A-containing receptors. AMPAR-mEPSC amplitudes were increased, indicating altered excitatory synaptic function. Behaviorally, Grin2b+/Δ mice exhibited hypoactivity, increased anxiety in males, and impaired sensorimotor gating in both sexes, while learning, memory, and social behaviors remained largely intact. These results demonstrate that a monoallelic GluN2B PTV alters NMDAR subunit composition and function, producing moderate behavioral effects, and provide insight into mechanisms underlying GRIN2B-associated ID."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Mental Retardation • Mood Disorders • Psychiatry • GRIN2A • GRIN2B

Stereoselective Synthesis of Conformationally Restricted γ- and β-Amino Alcohols as GluN2B Subtype-Selective NMDA Receptor Antagonists. (PubMed, J Med Chem) - "A series of γ- and β-amino alcohols 6 and 15 was designed to restrict the corresponding conformationally flexible substructures found in the prototypical GluN2B-specific NMDA receptor inhibitors Ro 25-6981 (1) and ifenprodil (2)...With respect to GluN2B affinity, inhibitory activity, ligand-lipophilicity efficiency (LLE), selectivity over σ1 receptors, and metabolic stability, β-amino alcohols cis-15a and trans-15b represent the most promising ligands of this series of compounds. However, both ligands displayed strong interactions with σ2 receptors indicating poor selectivity towards this receptor type."

Journal • GRIN2B

Ifenprodil inhibits nicotine-induced addiction-like behaviors in mice. (PubMed, Life Sci) - "These findings indicate that ifenprodil suppresses nicotine-related behaviors primarily in mice on a hyperdopaminergic (DAT-KO) background. Although further validation in wild-type models is warranted to clarify the translational generalizability of these findings, ifenprodil may be a novel approach for the treatment of nicotine addiction."

Journal • Preclinical • CNS Disorders • Nicotine Addiction • Psychiatry • GRIN2B

High-content imaging platforms for assessing neuroplasticity in early-stage drug discovery (Neuroscience 2025) - "Comparable effect sizes were observed with other test agents (ifenprodil, resveratrol, human EGF, and D159687) reproducibly, and consistent with their MoA. In conclusion, this platform provides a robust, flexible, and scalable tool for early-stage screening of neuroplasticity-modulating compounds, with clear relevance for neuropsychiatric and neurodegenerative drug discovery."

CNS Disorders • Psychiatry • BDNF

Mapping the Landscape of Diaschisis in Traumatic Brain Injury: A Scoping Review. (PubMed, Neurotrauma Rep) - "Interventions such as MK-801 and Ifenprodil showed potential to reverse diaschisis, but others had limited effects. This review underscores the limited but growing understanding of diaschisis in TBI. Targeted research on mild-to-moderate TBI, interventions, and imaging-validation trials is needed to improve diagnosis and treatment."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Vascular Neurology

Shentong Zhuyu Decoction Alleviates Neuropathic Pain in Mice by Inhibiting the NMDAR-2B Receptor-Mediated CaMKII/CREB Signaling Pathway in GABAergic Neurons of the Interpeduncular Nucleus. (PubMed, Pharmaceuticals (Basel)) - "High-dose STZYD (1.25 g·mL-1) and ifenprodil (6 mg·kg-1) reversed hyperalgesia and anxiety-like behaviors in spared nerve injury (SNI) mice, and microdialysis showed that STZYD and ifenprodil reduced the glutamate, D-serine, aspartate, glycine, and gamma-aminobutyric acid levels in the interpeduncular nucleus (IPN)...Molecular docking revealed the strong binding of licoricesaponin K2 and senkyunolide F to NMDAR-2B. STZYD exerts dose-dependent antinociceptive effects by modulating IPN GABAergic neuronal activity through the inhibition of the NMDAR-2B-mediated CaMKII/CREB pathway."

Journal • Preclinical • Neuralgia • Pain • Psychiatry • FOS • GRIN2B

Hydrolysis of O-, N-, and N+-glucuronide metabolites in human feces. (PubMed, Drug Metab Dispos) - "In this study, the stability of 5 representative O-, N-, and N+-glucuronides (ifenprodil O-glucuronide, valsartan N-glucuronide, candesartan N-glucuronide, camizestrant N-glucuronide, and clomipramine N+-glucuronide) was evaluated in pooled human feces in the presence or absence of β-glucuronidase inhibitors and in aqueous solutions at various pH levels. SIGNIFICANCE STATEMENT: This study demonstrates the rapid hydrolysis of 5 glucuronides to their parent drugs in human feces. The findings highlight the importance of analyzing early and late fecal pools in human absorption, distribution, metabolism, and excretion for drugs with prominent glucuronides in order to determine the origin of the parent drugs in feces."

Journal

Synthesis and Structure-Affinity Relationships of Receptor Ligands with 1,3-Dioxane Structure. (PubMed, Pharmaceuticals (Basel)) - "The affinity towards σ1 and σ2 receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies...The benzylamine 17a (Ki(σ1) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (Ki(σ1) = 154 nM, LLE = 6.72) represent the most promising σ1 ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies."

Journal

Neuropathic pain caused contextual fear generalization by reducing RIN1 expression in dorsal hippocampal CA1 pyramidal neurons. (PubMed, Neuropharmacology) - "Microinjection of GluN2B receptor-selective antagonist ifenprodil into the dorsal CA1 region attenuated the generalized contextual fear without significant influence on the auditory fear memory. Targeted knockdown of RIN1 in the dorsal CA1 pyramidal neurons mimicked the nerve injury by inducing the GluN2B receptor-dependent generalization of contextual fear. These data implicated the contextual fear generalization as one of the anxiety-related disorders during neuropathic pain and indicated an important role of RIN1 in the negative control over the generalized fear."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Neuralgia • Pain • Psychiatry • GRIN2B • RAS

Deciphering the role of MET/NMDAR complex in colorectal cancer pathogenesis (EACR 2025) - "To understand the biological role of this crosstalk in the HGF-driven invasive program, matrigel invasion and wound healing assays were performed in presence of two specific NMDAR (MK801 and Ifenprodil) and MET (JNJ-38877605) inhibitors. Overall, these data emphasize that MET/NMDAR crosstalk is involved in the CRC invasive program, suggesting that a combinatorial therapy targeting this complex may be exploited as a new therapeutic strategy."

Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • APC • GRIN2B • GRIN2D • MET

Quantification of NMDA GluN2B Receptors Occupancy by ifenprodil in Nonhuman Primates Using (S)-[18F]OF-NB1 PET (SNMMI 2025) - "No significant differences in administered (S)-[18F]OF-NB1 dose, injected mass, or plasma free fraction (fp) were observed among the four scanning sessions. The test–retest variability (TRV) of (S)-[18F]OF-NB1 VT values between baseline scans was 0.80+-7.9% (range: -12.3–7.9%) while the absolute TRV was 4.84% (range: 0.06–17.41%). Ifenprodil infusion produced a dose-dependent reduction in (S)-[18F]OF-NB1 binding across all examined brain regions."

Addiction (Opioid and Alcohol) • Chronic Cough • CNS Disorders • Cough • Depression • Developmental Disorders • Mental Retardation • Psychiatry • Respiratory Diseases • GRIN2B