Evidence map›Paper›PMID 27338081›Full record

ArticleMolecular pharmacology2016

Dihydromunduletone Is a Small-Molecule Selective Adhesion G Protein-Coupled Receptor Antagonist.

Hannah M Stoveken, Laura L Bahr, M W Anders, Andrew P Wojtovich, Alan V Smrcka, Gregory G Tall

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed
3.1field-weighted citation impact, top 8% 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

36 citing papers in PubMed, 65 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Adhesion G protein-coupled receptors.Pharmacological reviews · 2026
    Review
  5. Review
  6. GPCR drug discovery: new agents, targets and indications.Nature reviews. Drug discovery · 2025
    Review
  7. Review
  8. Article
  9. Review
  10. Article
  11. Article
  12. Review
  13. Review
  14. Article
  15. Ligands and Beyond: Mechanosensitive Adhesion GPCRs.Pharmaceuticals (Basel, Switzerland) · 2022
    Review
  16. Article
  17. Review
  18. Review
  19. 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

6 authors at 2 institutions in 1 country.

Hannah M StovekenDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.).
Laura L BahrDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.).
M W AndersDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.).
Andrew P WojtovichDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.).
Alan V SmrckaDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.).
Gregory G TallDepartment of Pharmacology and Physiology (H.M.S., L.L.B., M.W.A., A.P.W., A.V.S.), and Department of Anesthesiology (L.L.B., A.P.W.), University of Rochester Medical Center, Rochester, New York; and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (G.G.T.) gregtall@med.umich.edu.
University of Rochester Medical Center · USUniversity of Michigan–Ann Arbor · US

Funding

Regulation of Heterotrimeric G proteins by non-receptor activatorsR01GM088242 · NIGMS · UNIVERSITY OF ROCHESTER · PI TALL, GREGORY GORDON · 2009 to 2022
$4.2M
Mitochondrial ROS Microdomains and Neuronal IschemiaR01NS092558 · NINDS · UNIVERSITY OF ROCHESTER · PI WOJTOVICH, ANDREW PHILLIP · 2015 to 2025
$3.7M
Selective Targeting of G Protein beta gamma Subunits with Small MoleculesR01GM081772 · NIGMS · UNIVERSITY OF ROCHESTER · PI SMRCKA, ALAN V. · 2008 to 2017
$3.2M
Mechanisms of Adhesion GPCR ActionR01GM120110 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TALL, GREGORY GORDON · 2016 to 2023
$2.4M
NIGMS NIH HHS R01 GM081772NIGMS NIH HHS R01 GM088242NIGMS NIH HHS R01 GM120110NINDS NIH HHS R01 NS092558
6 · The paper itself

Abstract

Adhesion G protein-coupled receptors (aGPCRs) have emerging roles in development and tissue maintenance and is the most prevalent GPCR subclass mutated in human cancers, but to date, no drugs have been developed to target them in any disease. aGPCR extracellular domains contain a conserved subdomain that mediates self-cleavage proximal to the start of the 7-transmembrane domain (7TM). The two receptor protomers, extracellular domain and amino terminal fragment (NTF), and the 7TM or C-terminal fragment remain noncovalently bound at the plasma membrane in a low-activity state. We recently demonstrated that NTF dissociation liberates the 7TM N-terminal stalk, which acts as a tethered-peptide agonist permitting receptor-dependent heterotrimeric G protein activation. In many cases, natural aGPCR ligands are extracellular matrix proteins that dissociate the NTF to reveal the tethered agonist. Given the perceived difficulty in modifying extracellular matrix proteins to create aGPCR probes, we developed a serum response element (SRE)-luciferase-based screening approach to identify GPR56/ADGRG1 small-molecule inhibitors. A 2000-compound library comprising known drugs and natural products was screened for GPR56-dependent SRE activation inhibitors that did not inhibit constitutively active Gα13-dependent SRE activation. Dihydromunduletone (DHM), a rotenoid derivative, was validated using cell-free aGPCR/heterotrimeric G protein guanosine 5'-3-O-(thio)triphosphate binding reconstitution assays. DHM inhibited GPR56 and GPR114/ADGRG5, which have similar tethered agonists, but not the aGPCR GPR110/ADGRF1, M3 muscarinic acetylcholine, or β2 adrenergic GPCRs. DHM inhibited tethered peptide agonist-stimulated and synthetic peptide agonist-stimulated GPR56 but did not inhibit basal activity, demonstrating that it antagonizes the peptide agonist. DHM is a novel aGPCR antagonist and potentially useful chemical probe that may be developed as a future aGPCR therapeutic.

Indexed as

AnimalsBenzopyransCell AdhesionFlavonoidsHEK293 CellsHigh-Throughput Screening AssaysHumansPeptidesReceptors, G-Protein-CoupledReproducibility of ResultsRetinoidsSmall Molecule LibrariesBenzopyransdihydromunduletoneFlavonoidsPeptidesReceptors, G-Protein-CoupledRetinoidsSmall Molecule Libraries

Identifiers

PMID27338081
PMCPMC4998661
OpenAlexW2472354124

What OpenQuestion holds

Textmetadata
Read underepoch 390

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.