ifenprodil tartrate / Chiba University Hospital - LARVOL DELTA

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

The inhibitory effect of ifenprodil on nicotine-induced addictive behaviors (CINP-AsCNP 2025) - "These findings demonstrate that ifenprodil effectively reduces nicotine-induced reward behaviors and preference in mice, particularly in hyperdopaminergic DAT KO mice. However, given ifenprodil's broad pharmacological profile, the specific contribution of glutamatergic and GIRK-related mechanisms remains uncertain and warrants further investigation. Ifenprodil's established safety profile and current clinical applications in other conditions make it a promising candidate for nicotine addiction treatment."

CNS Disorders • Nicotine Addiction • Psychiatry • Tobacco Addiction • GRIN2B

Increase of the AMPA-evoked response in prefrontal cortex pyramidal neurons following acute administration of ketamine and S-ketamine in rats (CINP-AsCNP 2025) - "Although both R-ketamine and ifenprodil were shown to have an antidepressant-like effect in the forced swim test [3,4], they do not seem to increase AMPA-induced response in the PFC, unlike racemic and S-ketamine. However, the increase in AMPA-induced response might constitute a common factor underlining the antidepressant-like effects of ketamine and S-ketamine. Such an increase coincides with an enhancement in expression of GluA1 subunit of AMPA receptors in the PFC in rat [5]."

Preclinical • Anesthesia • CNS Disorders • Depression • Psychiatry • GRIN2B

Blocking the NR2B in the hippocampal dentate gyrus reduced the spatial memory deficits and apoptosis through the PERK-CHOP pathway in a rat model of sporadic Alzheimer's disease. (PubMed, Behav Brain Res) - "Microinjection of ifenprodil into the DG markedly inhibited the levels of p-PERK, p-eIF2α, CHOP, cleaved caspase-3, PARP, and neuronal apoptosis in the DG, while also ameliorating the spatial learning and memory impairments in sAD rats. These results suggest that NR2B in the hippocampal DG is associated with neuronal apoptosis via the PERK-CHOP pathway and contributes to the spatial learning and memory deficits observed in sAD rats."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • CASP3

NMDA receptor antagonists mitigate COVID-19-induced neuroinflammation and improve survival in a mouse model. (PubMed, Sci Rep) - "In a susceptible mouse model, animals inoculated with SARS-CoV-2 were pre-treated with either memantine or an alternative NMDAR antagonist, ifenprodil. Mice pre-treated with memantine showed improved survival when challenged with COVID-19 and a reduction in virus-induced neuroinflammatory impairments. Our findings support the further investigation of memantine for the prevention of COVID-19 induced neuroinflammation and resultant neurological symptoms and shed light on the possible protective mechanism of memantine in the elderly maintained on NMDAR antagonists."

Journal • Preclinical • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Novel 2-Pyrrolidone Derivatives as Negative Allosteric Modulators of GluN2B-Containing NMDA Receptors. (PubMed, ACS Med Chem Lett) - "This patent highlight describes a series of novel 2-pyrrolidone derivatives that act as negative allosteric modulators (NAMs) of GluN2B-containing N-methyl-d-aspartic acid receptors (NMDARs). These compounds target the ifenprodil binding site of the NMDA receptor and exhibit enhanced metabolic stability compared to traditional phenolic-based molecules."

Journal • GRIN2B

Role of Saponins from Platycodon grandiflorum in Alzheimer's Disease: DFT, Molecular Docking, and Simulation Studies in Key Enzymes. (PubMed, Molecules) - "The subsequent research from MD simulations of the best three docked compounds (polygalacin D2, polygalacin D, and platycodin D) suggested that their profiles match with the binding of standard active drugs like ifenprodil and donepezil to the six enzymes. The subtle differences between polygalacin D and D2, and platycodin D, were studied at the level of theory DFT/B3LYP, showing that the electron-donating effect of the hydroxy ethyl group in platycodin D rendering this compound of moderate electrophilicity and reactivity. Polygalacin D2 diglucoside substituent in position-2 contributed to its best binding and intermolecular interactions more than polygalacin D and prosapogenin D, which acted as the negative decoy drug."

Journal • Alzheimer's Disease • CNS Disorders • GSK3B

GluN2B influences the progression of status epilepticus by modulating calcium ion homeostasis through its interaction with CaMKIIα. (PubMed, Front Pharmacol) - "The GluN2B inhibitor ifenprodil was found to prolong the latency of epileptic seizures, counteract calcium influx, and modulate the expression of p-CaMKIIα, as well as the immune complex levels of GluN2B and CaMKIIα...When GluN2B binds to CaMKIIα, it may occupy the autophosphorylation site of CaMKIIα (T286 binding site), thereby affecting its autophosphorylation. This results in decreased phosphorylation levels, disruption of NMDAR-dependent calcium homeostasis, and alteration of the excitation/inhibition balance."

Journal • CNS Disorders • Epilepsy • GRIN2B

Ketamine prevents sevoflurane-induced excess cell-surface expression of α5GABAA receptors in mouse hippocampal neurons (IARS-SOCCA 2025) - "Ifenprodil increased cell-surface expression of α5GABAARs and tonic current. Ketamine alone had no effect on cell surface expression of α5GABAARs but prevented the increase caused by sevoflurane. We postulate the differing effects of ifenprodil and ketamine on α5GABAARs result partially from the drugs' action on NMDAR subtypes."

Preclinical • Anesthesia • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Major Depressive Disorder • Psychiatry

Ketamine prevents sevoflurane-induced excess cell-surface expression of α5GABAA receptors in mouse hippocampal neurons (IARS-SOCCA 2025) - "Ifenprodil increased cell-surface expression of α5GABAARs and tonic current. Ketamine alone had no effect on cell surface expression of α5GABAARs but prevented the increase caused by sevoflurane. We postulate the differing effects of ifenprodil and ketamine on α5GABAARs result partially from the drugs' action on NMDAR subtypes."

Preclinical • Anesthesia • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Major Depressive Disorder • Psychiatry

Upregulation of FMRP Is Involved in Neuropathic Pain by Regulating GluN2B Activation in Rat Spinal Cord. (PubMed, J Neurochem) - "Conversely, intrathecal administration of the GluN2B-specific inhibitor Ifenprodil significantly suppressed the CCI-induced increase in spinal FMRP expression...Furthermore, our results suggest a reciprocal regulatory relationship, indicating that GluN2B may also influence FMRP expression. This study provides insights into the molecular mechanisms underlying neuropathic pain, suggesting the potential for therapeutic intervention targeting the FMRP-GluN2B axis in pain management."

Journal • Preclinical • CNS Disorders • Immunology • Mental Retardation • Neuralgia • Pain • FMR1 • GRIN2B

Agmatine inhibits NMDA receptor-mediated calcium transients in mouse spinal cord dorsal horn via intact PSD95-nNOS signaling. (PubMed, J Pharmacol Exp Ther) - "In control spinal cord slices, ifenprodil inhibited NMDAr-mediated calcium transients, but it was not effective in GluN2B-KD...To determine whether the effect of agmatine could be attributed to an action downstream of the NMDAr (eg, neuronal nitric oxide synthase [nNOS]), we used the PSD95-nNOS tethering inhibitor, IC87201, to disrupt the link between NMDAr and nNOS...Agmatine reduces pain in preclinical models without the side effects of motor dysfunction or addiction. Clarifying the pharmacological mechanism of agmatine's analgesic effect in spinal neurotransmission may facilitate the development of novel pain-alleviating therapeutics."

Journal • Preclinical • CNS Disorders • Neuralgia • Pain • Psychiatry • DLG4 • GRIN2B

Design, synthesis, and evaluation of the pharmacological activity of novel NMDA receptor antagonists based on the germacrone scaffold. (PubMed, Bioorg Med Chem) - "The results revealed that compound C1 exhibited particularly outstanding activity, achieving a cell protection rate of 29.63 ± 1.56 % at a concentration of 0.05 μM, outperforming the positive control drug, ifenprodil...The results showed that compound C1 tightly bound to the active site of the NMDA receptor and possessed favorable pharmacokinetic properties. In conclusion, compound C1, characterized by a germacrone-linarinic acid structure, not only exhibits strong antagonistic effects on the NMDA receptor but also demonstrates excellent pharmacokinetic properties, indicating its potential for further development as a therapeutic drug for central nervous system diseases."

Journal

In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer's disease. (PubMed, Sci Rep) - "This study leverages advanced computational methods to screen 80 active constituents of Withania somnifera (Ashwagandha), a traditional herb known for its neuroprotective effects, against the NMDA receptor, using FDA-approved Ifenprodil as a reference...Furthermore, the compound affected the distance between LBD heterodimers and the tension within the LBD-M30 linker, demonstrating its potential to modulate NMDA receptor activity. This comprehensive study not only underscores the therapeutic promise of Withania somnifera derivatives for AD but also provides a detailed molecular basis for their efficacy, offering valuable insights for targeted drug development and innovative therapeutic strategies against Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • GRIN2B

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages. (PubMed, Mol Neurobiol) - "Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity...The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • GRIN2B