ArticleJournal of medicinal chemistry2006
Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists.
Article in Journal of medicinal chemistry, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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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
18 citing papers in PubMed, 45 citations in OpenAlex.
- Conformational energies of reference organic molecules: benchmarking of common efficient computational methods against coupled cluster theory.Journal of computer-aided molecular design · 2023Review
- Cryo-EM structure of the human adenosine AScience advances · 2022Article
- Double-headed nucleosides: Synthesis and applications.Beilstein journal of organic chemistry · 2021Review
- Neurotransmitters, Cell Types, and Circuit Mechanisms of Motor Skill Learning and Clinical Applications.Frontiers in neurology · 2021Review
- Breakthrough in GPCR Crystallography and Its Impact on Computer-Aided Drug Design.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Structural Probing and Molecular Modeling of the A₃ Adenosine Receptor: A Focus on Agonist Binding.Molecules (Basel, Switzerland) · 2017Review
- Probing GPCR structure: adenosine and P2Y nucleotide receptors.Methods in enzymology · 2013Article
- Click modification in the N6 region of A3 adenosine receptor-selective carbocyclic nucleosides for dendrimeric tethering that preserves pharmacophore recognition.Bioconjugate chemistry · 2012Article
- Remote control of neuronal signaling.Pharmacological reviews · 2011Review
- Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering.Handbook of experimental pharmacology · 2009Review
- Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways.Pharmacological research · 2008Article
- The Anti-Cancer Effect of AImmunology, endocrine & metabolic agents in medicinal chemistry · 2007Article
- Probing the binding site of the A1 adenosine receptor reengineered for orthogonal recognition by tailored nucleosides.Biochemistry · 2007Article
- Synthesis and biological evaluation of nucleoside analogues having 6-chloropurine as anti-SARS-CoV agents.Bioorganic & medicinal chemistry letters · 2007Article
- Neoceptors: reengineering GPCRs to recognize tailored ligands.Trends in pharmacological sciences · 2007Review
- Synthesis of N6-substituted 3'-ureidoadenosine derivatives as highly potent agonists at the mutant A3 adenosine receptor.Nucleosides, nucleotides & nucleic acids · 2007Article
- Adenosine receptors as therapeutic targets.Nature reviews. Drug discovery · 2006Review
- Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors.Nucleosides, nucleotides & nucleic acids · 2006Review
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3': amino, aminomethyl, azido, guanidino, ureido; and at 5': uronamido, azidodeoxy. N(6)-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N(6)-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC(50) = 0.18 microM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC(50) of 1.0 microM), but had no effect on the H272E mutant A(3)AR (100 microM). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.
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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.