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Study · Animal study (in vivo) · rat and mouse · 2024

11 results

The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron.

Sloop KW, Cox AL, Wainscott DB, White A, Droz BA, Stutsman C, Showalter AD, Suter TM, Dunbar JD, Snider BM, O'Farrell LS, Hewitt N and 11 more

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Ruble JC, Padgett LR, Woerly EM, Peterson JA, Coskun T, Liu Z, Coutant DE, Ai M, Emmerson PJ, Sangwung P, Willard FS

Science translational medicine18 Dec 2024Cited by 39 (Europe PMC)

PMID39693407 (opens in a new tab)DOI10.1126/scitranslmed.adp5765 (opens in a new tab)PepBankPUB-39693407
Publisher pagePubMedAsk about this study
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Summary

The text of this summary is not shown here, because the article license does not allow reuse. Read it at the source (opens in a new tab)

Text rights: Publisher copyright. Results still quote short attributed sentences.

Results from this study11

9 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Mechanism

    In mice expressing human GLP-1R, low orforglipron receptor occupancy yielded a full biological response.

    In plain wordsIn mice expressing human GLP-1R, low receptor occupancy by orforglipron produced a full biological response.

    Peptide
    Orforglipron
    Outcome
    Not applicableReceptor occupancy and biological response
    Study

    mousen: not reported in source

    Mice expressing human GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response.
    2 context sentences
    Summary · context
    To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test.
    Summary · context
    Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia.
  2. 02AnimalAnimal study (in vivo)Mechanism

    In gene-edited rats, pancreatic target engagement by orforglipron was consistent with peptide-based GLP-1R agonists.

    In plain wordsIn rats, orforglipron engagement in the pancreas was consistent with peptide-based GLP-1R agonists.

    Peptide
    Orforglipron
    Outcome
    Not applicablePancreatic target engagement
    Study

    ratn: not reported in source

    Glp1r S33W rats
    Comparator
    Peptide-based GLP-1R agonists
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (Glp1rS33W) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists.
  3. 03AnimalAnimal study (in vivo)Mechanism

    In gene-edited rats, brain target engagement by orforglipron was consistent with peptide-based GLP-1R agonists.

    In plain wordsIn rats, orforglipron engagement in the brain was consistent with peptide-based GLP-1R agonists.

    Peptide
    Orforglipron
    Outcome
    Not applicableBrain target engagement
    Study

    ratn: not reported in source

    Glp1r S33W rats
    Comparator
    Peptide-based GLP-1R agonists
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (Glp1rS33W) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists.
  4. 04AnimalAnimal study (in vivo)Efficacy outcome

    In rats with diet-induced obesity, studies compared weight loss with oral orforglipron and subcutaneous semaglutide without reporting relative magnitudes.

    In plain wordsIn rats with obesity, studies compared weight loss with oral orforglipron and injected semaglutide without reporting relative amounts.

    Peptide
    Orforglipron
    Outcome
    Direction not reportedBody weight
    Study

    ratn: not reported in source

    Diet-induced obesity in Glp1r S33W rats
    Comparator
    Subcutaneous semaglutide
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated · oralAs given in this study (rat).

    Source sentences

    Summary
    Diet-induced obesity in Glp1rS33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide.
  5. 05AnimalAnimal study (in vivo)Efficacy outcome

    In rats with diet-induced obesity, studies compared weight loss with subcutaneous semaglutide and oral orforglipron without reporting relative magnitudes.

    In plain wordsIn rats with obesity, studies compared weight loss with injected semaglutide and oral orforglipron without reporting relative amounts.

    Peptide
    Semaglutide
    Outcome
    Direction not reportedBody weight
    Study

    ratn: not reported in source

    Diet-induced obesity in Glp1r S33W rats
    Comparator
    Oral orforglipron
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated · subcutaneousAs given in this study (rat).

    Source sentences

    Summary
    Diet-induced obesity in Glp1rS33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide.
  6. 06LabIn vitro (cells)Mechanism

    In signal transduction assays, orforglipron showed low intrinsic efficacy for effector activation.

    In plain wordsIn lab tests, orforglipron showed low ability to activate effectors.

    Peptide
    Orforglipron
    Outcome
    Not applicableEffector activation efficacy
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment.
  7. 07LabIn vitro (cells)Mechanism

    In signal transduction assays, orforglipron showed negligible beta-arrestin recruitment.

    In plain wordsIn lab tests, orforglipron recruited negligible beta-arrestin.

    Peptide
    Orforglipron
    Outcome
    Not applicableBeta-arrestin recruitment
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment.
  8. 08LabIn vitro (cell-free)Activity measurement

    In binding experiments, orforglipron bound human GLP-1R with high affinity.

    In plain wordsIn lab tests, orforglipron bound human GLP-1R with high affinity.

    Peptide
    Orforglipron
    Outcome
    Not applicableGLP-1R binding affinity
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Measurements

    Inhibition constant
    1 nM
    human GLP-1R

    Source sentences

    Summary
    Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R.
  9. 09LabIn vitro (cell-free)Activity measurement

    In competition binding experiments, orforglipron was a selective ligand of human GLP-1R.

    In plain wordsIn lab tests, orforglipron selectively bound human GLP-1R.

    Peptide
    Orforglipron
    Outcome
    Not applicableHuman GLP-1R selectivity
    Study

    n: not reported in source

    Human GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R.

Studies that did not test the peptide alone2

In this study, the peptide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking the peptide.

  1. 10AnimalNot a test of Orforglipron aloneAnimal study (in vivo)Efficacy outcome

    In crossover studies, oral orforglipron sustained efficacy initiated by parenteral semaglutide.

    In plain wordsIn animals, oral orforglipron sustained efficacy that injected semaglutide initiated.

    Peptide
    Orforglipron
    Outcome
    Not applicableMaintenance of efficacy after crossover
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  2. 11AnimalNot a test of Semaglutide aloneAnimal study (in vivo)Efficacy outcome

    In crossover studies, oral orforglipron sustained efficacy initiated by parenteral semaglutide.

    In plain wordsIn animals, oral orforglipron sustained efficacy that injected semaglutide initiated.

    Peptide
    Semaglutide
    Outcome
    Not applicableMaintenance of efficacy after crossover
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide.

    In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 3Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 2

    14 Oct 2026, 01:46 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:06 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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