Species differences and mechanism of action of A3 adenosine receptor allosteric modulators
| العنوان: | Species differences and mechanism of action of A3 adenosine receptor allosteric modulators |
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| المؤلفون: | Tina C. Wan, Kenneth A. Jacobson, Lili Du, Zhan Guo Gao, Silvia Paoletta, Elizabeth T. Gizewski, Adriaan P. IJzerman, John A. Auchampach, Jacobus P. D. van Veldhoven, Samantha Barbour |
| المصدر: | Purinergic Signalling. 14:59-71 |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Agonist, medicine.drug_class, Allosteric regulation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Nucleoside, G protein-coupled receptor, Allosteric modulation, Molecular Biology, biology, Chemistry, Adenosine receptor, Cell Biology, Adenosine, Receptor–ligand kinetics, 030104 developmental biology, Allosteric enzyme, Mechanism of action, Biochemistry, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom, medicine.drug |
| الوصف: | Activity of the A(3) adenosine receptor (AR) allosteric modulators LUF6000 (2-cyclohexyl-N-(3,4-dichlorophenyl)-1H-imidazo [4,5-c]quinolin-4-amine) and LUF6096 (N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarbox-amide) was compared at four A(3)AR species homologs used in preclinical drug development. In guanosine 5'-[gamma-[S-35]thio]triphosphate ([S-35]GTP gamma S) binding assays with cell membranes isolated from human embryonic kidney cells stably expressing recombinant A(3)ARs, both modulators substantially enhanced agonist efficacy at human, dog, and rabbit A(3)ARs but provided only weak activity at mouse A(3)ARs. For human, dog, and rabbit, both modulators increased the maximal efficacy of the A(3)AR agonist 2-chloro-N (6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide as well as adenosine > 2-fold, while slightly reducing potency in human and dog. Based on results from N (6)-(4-amino-3-[I-125]iodobenzyl)adenosine-5'-N-methylcarboxamide ([I-125]I-AB-MECA) binding assays, we hypothesize that potency reduction is explained by an allosterically induced slowing in orthosteric ligand binding kinetics that reduces the rate of formation of ligand-receptor complexes. Mutation of four amino acid residues of the human A(3)AR to the murine sequence identified the extracellular loop 1 (EL1) region as being important in selectively controlling the allosteric actions of LUF6096 on [I-125]I-AB-MECA binding kinetics. Homology modeling suggested interaction between species-variable EL1 and agonist-contacting EL2. These results indicate that A(3)AR allostery is species-dependent and provide mechanistic insights into this therapeutically promising class of agents. |
| تدمد: | 1573-9546 1573-9538 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5509f6a3ecaa7b8820a71c7b34513f4 https://doi.org/10.1007/s11302-017-9592-1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e5509f6a3ecaa7b8820a71c7b34513f4 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 15739546 15739538 |
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