Background
IC87201 is an inhibitor of the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and post-synaptic density protein 95 (PSD-95).1 It inhibits the binding of PSD-95 to nNOS (IC50 = 31 ?M). IC87201 inhibits NMDA-induced cGMP production, a marker of PSD-95-dependent NOS activation, in primary rat hippocampal neurons (IC50 = 2.7 ?M). IC87201 (10 ?M) reduces MPP+-induced production of reactive oxygen species (ROS), cytochrome c release, and apoptosis in primary rat cortical neurons.2 In vivo, IC87201 decreases thermal hyperalgesia in mice (ED50 = 0.1 mg/kg), as well as mechanical allodynia in a rat model of neuropathic pain induced by chronic constriction injury (CCI). It also reduces immobility time in the forced swim and tail suspension tests in mice when administered at a dose of 1 mg/kg.3
1.Florio, S.K., Loh, C., Huang, S.M., et al.Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodentsBr. J. Pharmacol.158(2)494-506(2009)
2.Hu, W., Guan, L.-S., Dang, X.-B., et al.Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunctionNeurochem. Int.7957-64(2014)
3.Doucet, M.V., Levine, H., Dev, K.K., et al.Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in miceNeuropsychopharmacology38(8)1575-1584(2013)
Protocol
Animal experiment: | MK-801 is dissolved in saline and administered intraperitoneally (i.p.) in a within subjects dosing paradigm in order of increasing dose (0.1, 0.2, and 0.3 mg/kg). IC87201 (1, 4 and 10 mg/kg) and ZL006 (10 mg/kg) are dissolved in a vehicle containing 3% DMSO with the remaining 97% comprised of 1:1:18 of emulphor:ethanol:0.9% NaCl. Active compounds are compared with equivalent volumes of the appropriate vehicle in each case. MK-801, IC87201, and ZL006 are administered 30 min prior to behavioral testing. All drugs are administered intraperitoneally (i.p.) in a volume of 1 mL/kg[2]. |
参考文献: [1]. Bach A, et al. Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions. Sci Rep. 2015 Jul 16;5:12157.
[2]. Smith AE, et al. Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors. Behav Brain Res. 2016 May 15;305:23-9.
[3]. Doucet MV, et al. Small-molecule inhibitors at the PSD-95/nNOS interface protect against glutamate-induced neuronal atrophy in primary cortical neurons. Neuroscience. 2015 Aug 20;301:421-38. |
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