ArticleBMC pharmacology2008
Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000.
Article in BMC pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine.The Journal of biological chemistry · 2013Trial
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- Assessment of biased agonism at the ABiochemical pharmacology · 2020Article
- Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human AJournal of medicinal chemistry · 2020Article
- AMedicinal research reviews · 2018Review
- Species differences and mechanism of action of APurinergic signalling · 2018Article
- 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
- Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy.Cell death & disease · 2014Article
- A₃ adenosine receptor allosteric modulator induces an anti-inflammatory effect: in vivo studies and molecular mechanism of action.Mediators of inflammation · 2014Article
- Functional selectivity of adenosine A1 receptor ligands?Purinergic signalling · 2013Article
- Allosteric modulation and functional selectivity of G protein-coupled receptors.Drug discovery today. Technologies · 2013Review
- Protection from myocardial ischemia/reperfusion injury by a positive allosteric modulator of the A₃ adenosine receptor.The Journal of pharmacology and experimental therapeutics · 2012Article
- Functionally biased modulation of A(3) adenosine receptor agonist efficacy and potency by imidazoquinolinamine allosteric enhancers.Biochemical pharmacology · 2011Article
- International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.Pharmacological reviews · 2011Review
- Allosteric modulation of purine and pyrimidine receptors.Advances in pharmacology (San Diego, Calif.) · 2011Review
- UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation.Biochemical pharmacology · 2010Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundA series of 1H-imidazo- [4,5-c]quinolin-4-amine derivatives, represented by LUF6000 (N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo [4,5-c]quinolin-4-amine), are allosteric modulators of the human A3 adenosine receptor (AR). Here we studied the modulation by LUF6000 of the maximum effect (Emax) of structurally diverse agonists at the A3 AR stably expressed in CHO cells.
resultsIn an assay of [35S]GTPgammaS binding, the Emax of the A3 AR agonist Cl-IB-MECA at the A3 AR was lower than that of the non-selective AR agonist NECA. LUF6000 exerted an Emax-enhancing effect at a concentration of 0.1 microM or higher, and was shown to increase the Emax of Cl-IB-MECA and other low-efficacy agonists to a larger extent than that of the high-efficacy agonist NECA. Interestingly, LUF6000 converted a nucleoside A3 AR antagonist MRS542, but not a non-nucleoside antagonist MRS1220, into an agonist. LUF6000 alone did not show any effect. Mathematical modeling was performed to explain the differential effects of LUF6000 on agonists with various Emax. A simple explanation for the observation that LUF6000 has a much stronger effect on Cl-IB-MECA than on NECA derived from the mathematical modeling is that NECA has relatively strong intrinsic efficacy, such that the response is already close to the maximum response. Therefore, LUF6000 cannot enhance Emax much further.
conclusionLUF6000 was found to be an allosteric enhancer of Emax of structurally diverse agonists at the A3 AR, being more effective for low-Emax agonists than for high-Emax agonists. LUF6000 was demonstrated to convert an antagonist into an agonist, which represents the first example in G protein-coupled receptors. The observations from the present study are consistent with that predicted by mathematical modeling.
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Registered trials
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