IC87201 / Anagin, Indiana University - LARVOL DELTA

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

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

Post-stroke effects of IC87201 on neurobehavioral function and brain injuries: A stereological study. (PubMed, IBRO Neurosci Rep) - "The animals were randomized into sham, MCAO, MCAO+ DXM (Dextromethorphan hydrobromide monohydrate) as an NMDA antagonist, and MCAO+ IC87201 groups which in the last two groups, DXM (50 mg/kg) and IC87201 (10 mg/kg) were injected intraperitoneally after ischemia. IC87201 was successful in minimizing ischemia-induced damage, especially in the striatal region. In addition, IC87201, as a molecule that acts on the intracellular signaling cascade of the NMDA receptor, performed better than DXM, as an antagonist of this receptor."

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

The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries. (PubMed, Neurochem Res) - "Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research."

Journal • Cardiovascular • CNS Disorders • Vascular Neurology • DLG4

Agmatine inhibits NMDA receptor-mediated calcium transients in spinal cord dorsal horn through nNOS attenuation. (Neuroscience 2023) - "Ca2+ was imaged by two-photon microscopy and APV, ifenprodil, and agmatine were applied to spinal cord slices. Agmatine concentration-dependently attenuated the NMDARs-mediated Ca2+ transients, suggesting that agmatine is an effective inhibitor of NMDARs in the spinal cord dorsal horn, which is consistent with theresults from electrophysiological and neuropharmacological studies. Inhibition of PSD-95-nNOS tethering by application of IC87201 reversed the inhibition of NMDA-induced Ca2+ transients and thermal hyperalgesia consistent with agmatine's established inhibitory activity at nNOS."

CNS Disorders • DLG4 • GRIN2B

Downregulation of Preso protects against ischemic/reperfusion-mediated neuronal injury through regulating PSD95-nNOS/YAP pathways. (PubMed, Neurochem Int) - "In addition, the protective role of Preso knockdown against cerebral I/R injury was partly strengthened by IC87201, the nNOS/PSD95 interaction inhibitor, or weakened by Verteporfin (Vert), an inhibitor of YAP. In conclusion, Perso knockdown might exert a protective role against cerebral I/R injury via regulating PSD95-nNOS and YAP pathways, providing a potential therapeutic target for the treatment of ischemic stroke."

Journal • Cardiovascular • Ischemic stroke • Reperfusion Injury • DLG4

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

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