ArticleProceedings of the National Academy of Sciences of the United States of America2014
Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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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.
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.
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Who cites it
36 citing papers in PubMed, 111 citations in OpenAlex.
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- Molecular basis of ligand binding and receptor activation at the human ANature communications · 2025Article
- Structure-based discovery of positive allosteric modulators of the AProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Review
- Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery.Nature communications · 2023Article
- New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2.International journal of molecular sciences · 2023Article
- Small molecule allosteric modulation of the adenosine AFrontiers in endocrinology · 2023Review
- Investigation of adenosine A1 receptor-mediated β-arrestin 2 recruitment using a split-luciferase assay.Frontiers in pharmacology · 2023Article
- Selective activation of Gαob by an adenosine ANature communications · 2022Article
- International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update.Pharmacological reviews · 2022Review
- Molecular Simulations and Drug Discovery of Adenosine Receptors.Molecules (Basel, Switzerland) · 2022Review
- Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CBFrontiers in chemistry · 2022Article
- Positive allosteric mechanisms of adenosine ANature · 2021Article
- Pharmacological Insights Into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure.Frontiers in pharmacology · 2021Article
- Allosteric Antagonism of the ACells · 2020Article
- 2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts.Journal of medicinal chemistry · 2020Article
- The effect of two selective ABritish journal of pharmacology · 2020Article
- Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine AComputational and structural biotechnology journal · 2020Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of on-target bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)--a hybrid molecule comprising adenosine linked to a positive allosteric modulator--specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.
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Registered trials
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.