Evidence map›Paper›PMID 41332641›Full record

ArticlebioRxiv : the preprint server for biology2025

A reversible allosteric inhibitor of GlyT2 alleviates neuropathic pain without on-target side effects.

Ryan P Cantwell Chater, Julian Peiser-Oliver, Tanmay K Pati, Ada S Quinn, Irina Lotsaris, Zachary J Frangos, Kristen E Anderson, Anna E Tischer, Billy J Williams-Noonan, Karin R Aubrey and 6 more

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In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors.

Ryan P Cantwell ChaterDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0003-2301-6841
Julian Peiser-OliverSchool of Medical Sciences, University of Sydney, Sydney, NSW, Australia.ORCID 0009-0009-1615-6572
Tanmay K PatiDepartment of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, USA.ORCID 0000-0001-5652-4442
Ada S QuinnAustralian Institute of Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.ORCID 0009-0003-1862-0750
Irina LotsarisSchool of Medical Sciences, University of Sydney, Sydney, NSW, Australia.ORCID 0000-0001-5627-9897
Zachary J FrangosBiobehavioral Imaging & Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.ORCID 0000-0002-5499-4050
Kristen E AndersonPain Management Research Institute, Kolling Institute, Royal North Shore Hospital NSLHD, St Leonards, New South Wales, Australia.
Anna E TischerBiobehavioral Imaging & Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.ORCID 0009-0001-4268-5904
Billy J Williams-NoonanAustralian Institute of Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.ORCID 0000-0002-6900-3862
Karin R AubreyPain Management Research Institute, Kolling Institute, Royal North Shore Hospital NSLHD, St Leonards, New South Wales, Australia.
Megan L O'MaraAustralian Institute of Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.ORCID 0000-0002-8764-1585
Michael MichaelidesBiobehavioral Imaging & Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.ORCID 0000-0003-0398-4917
Sarasa A MohammadiFaculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.ORCID 0000-0002-8351-8635
Christopher L CioffiDepartment of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, USA.ORCID 0000-0003-0642-7905
Robert J VandenbergSchool of Medical Sciences, University of Sydney, Sydney, NSW, Australia.ORCID 0000-0003-1523-4814
Azadeh ShahsavarDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0001-5405-597X

Funding

Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic painR01DA048879 · NIDA · RENSSELAER POLYTECHNIC INSTITUTE · PI CIOFFI, CHRISTOPHER L., VANDENBERG, ROBERT JOHN · 2019 to 2022
$1.8M
NIDA NIH HHS R01 DA048879
6 · The paper itself

Abstract

Chronic neuropathic pain, caused by nerve damage or disease, is increasing in prevalence, but current treatments are ineffective and over-reliant on opioids. The neuronal glycine transporter, GlyT2, regulates inhibitory glycinergic neurotransmission and represents a promising target for new analgesics. However, most GlyT2 inhibitors cause significant side effects, in part due to irreversible inhibition at analgesic doses. Here we develop a reversible inhibitor of GlyT2, RPI-GLYT2-82, and identify its binding site by determining cryo-EM structures of human GlyT2. We capture three fundamental conformational states of GlyT2 in the substrate-free state, and bound to either glycine, RPI-GLYT2-82 or the pseudo-irreversible inhibitor ORG25543. We demonstrate that RPI-GLYT2-82 dissociates from GlyT2 faster than ORG25543, providing analgesia in mouse neuropathic pain models without on-target side-effects or addiction liability. Our data provide a mechanistic understanding of allosteric inhibition of glycine transport, enabling structure-based design of non-opioid analgesics.

Identifiers

PMID41332641
PMCPMC12667952

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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.