ArticleBioorganic & medicinal chemistry2004
Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands.
Article in Bioorganic & medicinal chemistry, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 56 citations in OpenAlex.
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- 2-Phenethylamines in Medicinal Chemistry: A Review.Molecules (Basel, Switzerland) · 2023Review
- Biological Evaluation of 5'-(ACS medicinal chemistry letters · 2021Article
- 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
- Structural Probing and Molecular Modeling of the A₃ Adenosine Receptor: A Focus on Agonist Binding.Molecules (Basel, Switzerland) · 2017Review
- John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors.Computational and structural biotechnology journal · 2015Review
- In vivo phenotypic screening for treating chronic neuropathic pain: modification of C2-arylethynyl group of conformationally constrained A3 adenosine receptor agonists.Journal of medicinal chemistry · 2014Article
- Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.Bioconjugate chemistry · 2014Article
- Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.Bioorganic & medicinal chemistry letters · 2014Article
- Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase.Bioorganic & medicinal chemistry · 2013Article
- Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A₂A adenosine receptor.Journal of medicinal chemistry · 2012Article
- Structure of an agonist-bound human A2A adenosine receptor.Science (New York, N.Y.) · 2011Article
- Synthesis and pharmacological characterization of [(125)I]MRS5127, a high affinity, selective agonist radioligand for the A3 adenosine receptor.Biochemical pharmacology · 2010Article
- Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.Journal of the American Chemical Society · 2010Article
- Evaluation of homology modeling of G-protein-coupled receptors in light of the A(2A) adenosine receptor crystallographic structure.Journal of medicinal chemistry · 2009Article
- Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering.Handbook of experimental pharmacology · 2009Review
- Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B.Bioorganic & medicinal chemistry letters · 2008Article
- Probing distal regions of the A2B adenosine receptor by quantitative structure-activity relationship modeling of known and novel agonists.Journal of medicinal chemistry · 2008Article
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9 authors at 2 institutions in 1 country.
Funding
Abstract
We synthesized phenyl ring-substituted analogues of N(6)-(1S,2R)-(2-phenyl-1-cyclopropyl)adenosine, which is highly potent in binding to the human A(3)AR with a Ki value of 0.63 nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA(3)AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A(3)AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phe168) in the putative A(3)AR binding site around the phenyl moiety. A heteroaromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A(3)AR binding. Other related N(6)-substituted adenosine derivatives were included for comparison. Although the N(6)-(2-phenyl-1-cyclopropyl) derivatives were full A(3)AR agonists, several other derivatives had greatly reduced efficacy. N(6)-Cyclopropyladenosine was an A(3)AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N(6)-(2,2-Diphenylethyl)adenosine was an A(3)AR antagonist, and either adding a bond between the two phenyl rings (N(6)-9-fluorenylmethyl) or shortening the ethyl moiety (N(6)-diphenylmethyl) restored efficacy. A QSAR study of the N(6) region provided a model that was complementary to the putative A(3)AR binding site in a rhodopsin-based homology model. Thus, a new series of high-affinity A(3)AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches.
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