ArticleMolecular pharmacology2014
The second extracellular loop of the adenosine A1 receptor mediates activity of allosteric enhancers.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 20 citations in OpenAlex.
- From empirical screening to lipid trolling: the evolution of extrahelical allosteric modulators of AMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Identification of a β-arrestin-biased negative allosteric modulator for the βProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Small molecule allosteric modulation of the adenosine AFrontiers in endocrinology · 2023Review
- Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.ACS pharmacology & translational science · 2021Article
- New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism.British journal of pharmacology · 2018Review
- Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.Journal of computational chemistry · 2017Article
- Mechanistic insights into allosteric structure-function relationships at the M1 muscarinic acetylcholine receptor.The Journal of biological chemistry · 2014Article
- Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A2A Adenosine Receptor.ACS medicinal chemistry letters · 2014Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Allosteric enhancers of the adenosine A1 receptor amplify signaling by orthosteric agonists. Allosteric enhancers are appealing drug candidates because their activity requires that the orthosteric site be occupied by an agonist, thereby conferring specificity to stressed or injured tissues that produce adenosine. To explore the mechanism of allosteric enhancer activity, we examined their action on several A1 receptor constructs, including (1) species variants, (2) species chimeras, (3) alanine scanning mutants, and (4) site-specific mutants. These findings were combined with homology modeling of the A1 receptor and in silico screening of an allosteric enhancer library. The binding modes of known docked allosteric enhancers correlated with the known structure-activity relationship, suggesting that these allosteric enhancers bind to a pocket formed by the second extracellular loop, flanked by residues S150 and M162. We propose a model in which this vestibule controls the entry and efflux of agonists from the orthosteric site and agonist binding elicits a conformational change that enables allosteric enhancer binding. This model provides a mechanism for the observations that allosteric enhancers slow the dissociation of orthosteric agonists but not antagonists.
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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.