Evidence map›Paper›PMID 26071110›Full record

ArticleNeuropharmacology2015

Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics.

Wan-Hung Lee, Zhili Xu, Nicole M Ashpole, Andy Hudmon, Pushkar M Kulkarni, Ganesh A Thakur, Yvonne Y Lai, Andrea G Hohmann

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuropharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
4.1field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 66 citations in OpenAlex.

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  12. A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABANeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021
    Article
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  18. RGS4 Maintains Chronic Pain Symptoms in Rodent Models.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019
    Article
  19. PDZ Domains as Drug Targets.Advanced therapeutics · 2019
    Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 4 institutions in 1 country.

Wan-Hung LeeBiochemistry Interdisciplinary Graduate Program, Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA.
Zhili XuDepartment of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
Nicole M AshpoleDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Andy HudmonDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Pushkar M KulkarniCenter for Drug Discovery, and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
Ganesh A ThakurCenter for Drug Discovery, and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
Yvonne Y LaiDepartment of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
Andrea G HohmannBiochemistry Interdisciplinary Graduate Program, Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Bloomington, IN, USA. Electronic address: hohmanna@indiana.edu.
Indiana University Bloomington · USNortheastern University · USIndiana University – Purdue University Indianapolis · USIndiana University School of Medicine

Funding

Indiana Clinical and Translational Science Institute (UL1)UL1TR000006 · NCATS · INDIANA UNIVERSITY INDIANAPOLIS · PI SHEKHAR, ANANTHA · 2012 to 2013
$5.6M
Protein-protein interaction inhibitors as novel analgesicsR21DA037673 · NIDA · TRUSTEES OF INDIANA UNIVERSITY · PI HOHMANN, ANDREA GRACE · 2013 to 2014
$429k
A rodent model of episodic memoryR01MH098985 · NIMH · TRUSTEES OF INDIANA UNIVERSITY · PI CRYSTAL, JONATHON D · 2013 to 2013
$387k
NCATS NIH HHS UL1 TR000006NIDA NIH HHS DA 037673NIDA NIH HHS R21 DA037673NIMH NIH HHS R01 MH098985
6 · The paper itself

Abstract

Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) and generating nitric oxide (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS to NMDARs, the PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 μM) and ZL006 (EC50: 12.88 μM) directly inhibited binding of purified PSD95 and nNOS proteins in AlphaScreen without altering binding of PSD95 to ErbB4. Both PSD95-nNOS inhibitors suppressed glutamate-induced cell death with efficacy comparable to MK-801. IC87201 and ZL006 preferentially suppressed phase 2A pain behavior in the formalin test and suppressed allodynia induced by intraplantar complete Freund's adjuvant administration. IC87201 and ZL006 suppressed mechanical and cold allodynia induced by the chemotherapeutic agent paclitaxel (ED50s: 2.47 and 0.93 mg/kg i.p. for IC87201 and ZL006, respectively). Efficacy of PSD95-nNOS disruptors was similar to MK-801. Motor ataxic effects were induced by MK-801 but not by ZL006 or IC87201. Finally, MK-801 produced hyperalgesia in the tail-flick test whereas IC87201 and ZL006 did not alter basal nociceptive thresholds. Our studies establish the utility of using AlphaScreen and purified protein pairs to establish and quantify disruption of protein-protein interactions. Our results demonstrate previously unrecognized antinociceptive efficacy of ZL006 and establish, using two small molecules, a broad application for PSD95-nNOS inhibitors in treating neuropathic and inflammatory pain. Collectively, our results demonstrate that disrupting PSD95-nNOS protein-protein interactions is effective in attenuating pathological pain without producing unwanted side effects (i.e. motor ataxia) associated with NMDAR antagonists.

Indexed as

Aminosalicylic AcidsAnalgesicsAnimalsAtaxiaBenzylaminesBrainCell DeathCells, CulturedChlorophenolsDisease Models, AnimalDizocilpine MaleateDose-Response Relationship, DrugHyperalgesiaIntracellular Signaling Peptides and ProteinsMaleMembrane Proteins2-((1H-benzo(d)(1,2,3)triazol-5-ylamino)methyl)-4,6-dichlorophenolAminosalicylic AcidsAnalgesicsBenzylaminesChlorophenolsDizocilpine MaleateIntracellular Signaling Peptides and ProteinsMembrane ProteinsNeuroprotective AgentsNitric Oxide Synthase Type ITriazolesZL006 compoundAllodyniaCentral sensitizationComplete Freund's adjuvantmotor ataxiaNeuronal nitric oxide synthaseNeuropathic painNMDARpaclitaxelPostsynaptic density 95

Identifiers

PMID26071110
PMCPMC4539046
OpenAlexW597969357

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.