2-Aryladenine derivatives as a potent scaffold for A1, A3 and dual A1/A3 adenosine receptor antagonists: Synthesis and structure-activity relationships

Areias, Filipe; Correia, Carla; Rocha, Ashly; Brea, José; Castro, Marián; Loza, Marı́a Isabel; Proença, M. Fernanda; Carvalho, M. Alice

doi:10.1016/j.bmc.2019.06.034

Cited by 5 publications

(8 citation statements)

References 14 publications

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“…It has also been suggested that the A 3 R is over expressed in various tumour cells suggesting it may be a viable drug target against cancer proliferation [4][5][6] . While a number of novel potent and selective A 3 R antagonists have been previously described [7][8][9] , one of the challenges associated with the druggability of the AR family has been the targeting of individual subtypes with sufficient specificity to limit off-target side effects 10 . Although all AR members are activated by the endogenous agonist adenosine, the A 2A R and A 2B R are predominantly G s -coupled whereas A 1 R and A 3 R generally couple to G i/o .…”

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confidence: 99%

Pharmacological characterisation of novel adenosine A3 receptor antagonists

Barkan

Lagarias

Stampelou

et al. 2020

Sci Rep

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The adenosine A3 receptor (A3R) belongs to a family of four adenosine receptor (AR) subtypes which all play distinct roles throughout the body. A3R antagonists have been described as potential treatments for numerous diseases including asthma. Given the similarity between (adenosine receptors) orthosteric binding sites, obtaining highly selective antagonists is a challenging but critical task. Here we screen 39 potential A3R, antagonists using agonist-induced inhibition of cAMP. Positive hits were assessed for AR subtype selectivity through cAMP accumulation assays. The antagonist affinity was determined using Schild analysis (pA2 values) and fluorescent ligand binding. Structure–activity relationship investigations revealed that loss of the 3-(dichlorophenyl)-isoxazolyl moiety or the aromatic nitrogen heterocycle with nitrogen at α-position to the carbon of carboximidamide group significantly attenuated K18 antagonistic potency. Mutagenic studies supported by molecular dynamic simulations combined with Molecular Mechanics—Poisson Boltzmann Surface Area calculations identified the residues important for binding in the A3R orthosteric site. We demonstrate that K18, which contains a 3-(dichlorophenyl)-isoxazole group connected through carbonyloxycarboximidamide fragment with a 1,3-thiazole ring, is a specific A3R (< 1 µM) competitive antagonist. Finally, we introduce a model that enables estimates of the equilibrium binding affinity for rapidly disassociating compounds from real-time fluorescent ligand-binding studies. These results demonstrate the pharmacological characterisation of a selective competitive A3R antagonist and the description of its orthosteric binding mode. Our findings may provide new insights for drug discovery.

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confidence: 99%

Pharmacological characterisation of novel adenosine A3 receptor antagonists

Barkan

Lagarias

Stampelou

et al. 2020

Sci Rep

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“…The target compounds 3a–x were synthesized through the synthetic approach described in Scheme 1 . The starting reagents 1 [ 29 ] and 2 [ 28 , 30 ] were obtained following the procedures described in previous work. Briefly, the commercially available diaminomaleonitrile was treated with triethyl orthoformate, under reflux.…”

Section: Resultsmentioning

confidence: 99%

“…Based on their structural similarity, we can generalize that all compounds of this work are antagonists of adenosine receptors. In this work, we synthesized highly potent and selective hits based on the scaffold for adenosine receptor antagonists identified in our previous publication [28]. These results indicate that the purines substituted with a morpholine group at C-6, a hydrogen atom or a methyl group at N-9, and a specific aryl group at C-2 of purine nucleus, gave high affinity and selective antagonists for adenosine A 1 and A 3 receptors, as well as dual antagonists for receptors A 1 /A 2A , A 1 /A 2B , and A 1 /A 3 .…”

Section: Pharmacologymentioning

confidence: 99%

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2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives

Areias,

Correia,

Rocha

et al. 2024

Molecules

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A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.

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“…Determining what alterations tumor cells undergo when simultaneously inhibiting both hA 1 and hA 3 AR that share a sub-signal transduction will be an important step in the development of anticancer drugs targeting adenosine receptors. Several studies on ligands that simultaneously regulate hA 1 and hA 3 AR have been published [20][21][22]. Compound 1 bearing a purine scaffold shows an inhibition constant (K i ) of 6.8 and 6.3 nM, and compound 2 shows a K i of 36.7 and 25.4 nM for hA 1 and hA 3 AR, respectively, indicating balanced binding (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor

et al. 2022

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Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

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2-Aryladenine derivatives as a potent scaffold for A1, A3 and dual A1/A3 adenosine receptor antagonists: Synthesis and structure-activity relationships

Cited by 5 publications

References 14 publications

Pharmacological characterisation of novel adenosine A3 receptor antagonists

Pharmacological characterisation of novel adenosine A3 receptor antagonists

2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor

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