Discovery of Potent and Highly Selective A<sub>2B</sub> Adenosine Receptor Antagonist Chemotypes

Maatougui, Abdelaziz El; Azuaje, Jhonny; González‐Gómez, Manuel; Miguez, Gabriel Eduardo; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; Garcı́a-Mera, Xerardo; Gutiérrez‐de‐Terán, Hugo; Sotelo, Eddy

doi:10.1021/acs.jmedchem.5b01586

Cited by 59 publications

(119 citation statements)

References 46 publications

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“…During the last years, our labs have combined FEP and other computational methodologies with high-throughput synthetic methodologies and pharmacological characterization, to develop various series of structurally simple, novel AR ligands [ 23 ]. Our SBDD protocol includes homology modeling, protein–ligand docking, 3D-QSAR, MD and FEP simulations, and was used to assist the design of novel ligands as well as to predict or rationalize their pharmacological profile [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. The different series obtained with this strategy, represented in Figure 1 , have been optimized to yield potent and selective antagonists of the different ARs.…”

Section: Introductionmentioning

confidence: 99%

“…The first scaffold reported, a 2,4-diarylpyrimidine, was recently followed by a bioisosteric series of 2,4-diarylpyridines, both of them revealing high affinity and selectivity as A 3 AR antagonists [ 24 , 25 , 30 ]. For the A 2B receptor, we have documented the first non-planar, enantioselective antagonists, and disclosed the reasons of their enantiospecificity [ 31 , 32 ]. The A 2A AR emerges as the most attractive target for SBDD within the AR family, due to the existence of several crystal structures complemented with broad mutagenesis and SAR data.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

et al. 2017

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The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A1AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A2AAR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

et al. 2017

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“…Due to demonstrated treatment options (PD and cancer immunotherapy), novel A 2A AdR antagonists with improved physicochemical, pharmacokinetic and pharmacological properties are being progressively developed . Additionally, new highly selective A 2B AdR antagonists are progressively being identified and some promising drug candidates are under evaluation in clinical trials for the treatment of diabetes, asthma and chronic obstructive pulmonary disease …”

Section: Adverse Effects and Toxicity Of Adenosine Receptor Ligandsmentioning

confidence: 99%

“…[88] Additionally, new highly selective A 2B AdR antagonists are progressively being identified and some promising drug candidates are under evaluation in clinical trials for the treatment of diabetes, asthma and chronic obstructive pulmonary disease. [89] Selected example of metabolic activation and genotoxicity…”

Section: Recent Pharmaceutical Developments Of a 2a Adr Antagonists Amentioning

confidence: 99%

Safety issues of compounds acting on adenosinergic signalling

Schmidt

Ferk

2017

Journal of Pharmacy and Pharmacology

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Objectives Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. Key findings Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. Summary Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

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“…Sequence analysis of the human A 2A and A 2B ARs revealed the largest differences in the loop regions, especially in the extracellular loop 2 (ECL2) [11]. The endogenous ligand adenosine and its derivatives NECA (2) and CGS21680 (3) show significantly higher affinity for the A 2A AR than for the A 2B receptor subtype, despite very similar ligand binding sites of both receptors [12,13]. The structural reason for this striking difference is unknown.…”

Section: Introductionmentioning

confidence: 99%

Role of extracellular cysteine residues in the adenosine A2A receptor

Filippo

Namasivayam

Zappe

et al. 2016

Purinergic Signalling

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The G protein-coupled A2A adenosine receptor represents an important drug target. Crystal structures and modeling studies indicated that three disulfide bonds are formed between ECL1 and ECL2 (I, Cys71(2.69)-Cys159(45.43); II, Cys74(3.22)-Cys146(45.30), and III, Cys77(3.25)-Cys166(45.50)). However, the A2BAR subtype appears to require only disulfide bond III for proper function. In this study, each of the three disulfide bonds in the A2AAR was disrupted by mutation of one of the cysteine residues to serine. The mutant receptors were stably expressed in Chinese hamster ovary cells and analyzed in cyclic adenosine monophosphate (cAMP) accumulation and radioligand binding studies using structurally diverse agonists: adenosine, NECA, CGS21680, and PSB-15826. Results were rationalized by molecular modeling. The observed effects were dependent on the investigated agonist. Loss of disulfide bond I led to a widening of the orthosteric binding pocket resulting in a strong reduction in the potency of adenosine, but not of NECA or 2-substituted nucleosides. Disruption of disulfide bond II led to a significant reduction in the agonists' efficacy indicating its importance for receptor activation. Disulfide bond III disruption reduced potency and affinity of the small adenosine agonists and NECA, but not of the larger 2-substituted agonists. While all the three disulfide bonds were essential for high potency or efficacy of adenosine, structural modification of the nucleoside could rescue affinity or efficacy at the mutant receptors. At present, it cannot be excluded that formation of the extracellular disulfide bonds in the A2AAR is dynamic. This might add another level of G protein-coupled receptor (GPCR) modulation, in particular for the cysteine-rich A2A and A2BARs.

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Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes

Cited by 59 publications

References 46 publications

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Safety issues of compounds acting on adenosinergic signalling

Role of extracellular cysteine residues in the adenosine A2A receptor

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Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes

Cited by 59 publications

References 46 publications

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Safety issues of compounds acting on adenosinergic signalling

Role of extracellular cysteine residues in the adenosine A2A receptor

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Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes